Hydrogenated 1-benzooxacycloalkylpyridinecarboxylic acid compounds and compositions

ABSTRACT

The invention relates to novel hydrogenated 1-benzooxacycloalkylpyridinecarboxylic acid compounds of formula ##STR1## in which the variables R 1 , R 2 , R 3 , R 4 , R 5 , alk, X, Z, m, n and p, the dotted line and the substituents of the ring A have the meanings indicated in the specification and in the claims, and to their tautomers and/or salts. These compounds can be used as pharmaceutical active ingredients and can be prepared in a manner known per se.

This is a divisional of application Ser. No. 288,332, filed on Dec. 21,1988, now U.S. Pat. No. 4,957,928, which is a continuation-in-part ofSer. No. 063,188, filed Jun. 16, 1987, now abandoned.

The invention relates to novel hydrogenated1-benzooxacycloalkylpyridinecarboxylic acid compounds of the formula##STR2## in which alk is lower alkylene or lower alkylidene, the dottedline is intended to indicate the presence of a single or a double bondbetween the carbon atoms carrying the substituents R₁ and R₂, R₃ ishydrogen or lower alkyl, R₄ is lower alkyl, R₅ is lower alkyl, and inwhich (A) either R₁ represents carboxy, lower alkoxycarbonyl, carbamoyl,N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl or optionallyacylated hydroxymethyl and R₂ represents hydrogen, an optionallyetherified or acylated hydroxy group or an optionally acylated aminogroup, or R₁ represents hydrogen and R₂ represents carboxy, loweralkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl or optionally acylated hydroxymethyl, and in which the ring Ais unsubstituted or is mono- or poly-substituted by hydroxy, loweralkoxy, lower alkanoyloxy, halogen, lower alkyl and/or bytrifluoromethyl, p is 0, m is 1, and in which either each of X and Z isan oxygen atom and n is 1, or X is a methylene group, Z is an oxygenatom and n is 1, or X is an oxygen atom, Z is a methylene group and n is1, or X is a direct bond, Z is an oxygen atom and n is 2, with theproviso, that R₂ is different from carbamoyl, if R₁ is hydrogen, R₃ ishydrogen, alk is methylene, ethylene or 1,3-propylene, the ring A isunsubstituted or is monosubstituted in the 6- or 7-position or isdisbustituted in the 6- and 7-position, substituents being selected fromthe group consisting of lower alkoxy, halogen, lower alkyl andtrifluoromethyl, the dotted line is intended to indicate the presence ofa single bond, each of X and Z is an oxygen atom, and n is 1, or if R₁represents hydrogen, R₃ is hydrogen, alk represents ethylidene, the ringA is unsubstituted, the dotted line is intended to indicate the presenceof a single bond, each of X and Z is an oxygen atom, and n is 1, or inwhich (B) either R₁ is carboxy, lower alkoxycarbonyl, amidated carboxyor free or acylated hydroxymethyl and R₂ is hydrogen, a free, etherifiedor acylated hydroxy group or a free or acylated amino group, or R₁ ishydrogen and R₂ is carboxy, lower alkoxycarbonyl, amidated carboxy orfree or acylated hydroxymethyl, and in which the ring A is unsubstitutedor is mono- or poly-substituted by hydroxy, lower alkoxy, loweralkanoyloxy, cyano, halogen, lower alkyl and/or by trifluoromethyl, p is1, m is 0 or 1, Z is an oxygenatom, and in which either X is an oxygenatom or a methylene group and n is 0, or X is a direct bond and n is 1,and to their tautomers and/or salts, to the use of these compounds, to aprocess for the preparation thereof, and to pharmaceutical compositionscontaining a compound of formula I or a tautomer and/or apharmaceutically acceptable salt thereof.

The invention relates especially to the groups of compounds of theformula I which is made up by the compounds of the formula ##STR3## inwhich either R₁ represents carboxy, lower alkoxycarbonyl, carbamoyl,N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl or optionallyacylated hydroxymethyl and R₂ represents hydrogen, an optionallyetherified or acylated hydroxy group or an optionally acylated aminogroup, or R₁ represents hydrogen and R₂ represents carboxy, loweralkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl or optionally acylated hydroxymethyl, R₃ represents hydrogenor lower alkyl, alk represents lower alkylene or lower alkylidene, thering A is unsubstituted or is mono- or poly-substituted by hydroxy,lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or bytrifluoromethyl, the dotted line is intended to indicate the presence ofa single or a double bond, and either each of X and Y represents anoxygen atom and n represents 1, or X represents a methylene group, Yrepresents an oxygen atom and n represents 1, or X represents an oxygenatom, Y represents a methylene group and n represents 1, or X representsa direct bond, Y represents an oxygen atom and n represents 2, with theproviso that R₂ is different from carbamoyl, if R₁ represents hydrogen,R₃ is hydrogen, alk represents methylene, ethylene or 1,3-propylene, thering A is unsubstituted or is monosubstituted in the 6- or 7-position oris disubstituted in the 6- and 7-position, substituents being selectedfrom the group consisting of lower alkoxy, halogen, lower alkyl andtrifluormethyl, the dotted line is intended to indicate the presence ofa single bond, each of X and Y represents an oxygen atom and nrepresents 1, or if R₁ represents hydrogen, R₃ is hydrogen, alkrepresents ethylidene, the ring A is unsubstituted, the dotted line isintended to indicate the presence of a single bond, each of X and Yrepresents an oxygen atom and n represents 1; and to their tautomersand/or salts, to the use of these compounds, to processes for theirmanufacture and to pharmaceutical compositions containing a compound ofthe formula IA or a tautomer and/or a pharmaceutically acceptable saltthereof.

The invention relates also especially to the group of compounds of theformula I which is made up by the compounds of the formula ##STR4## inwhich either R₁ is carboxy, lower alkoxycarbonyl, amidated carboxy orfree or acylated hydroxymethyl and R₂ is hydrogen, a free, etherified oracylated hydroxy group or a free or acylated amino group, or R₁ ishydrogen and R₂ is carboxy, lower alkoxycarbonyl, amidated carboxy orfree or acylated hydroxymethyl, and in which R₃ is hydrogen or loweralkyl, R₄ is lower alkyl, R₅ is lower alkyl, alk is lower alkylene orlower alkylidene, the ring A is unsubstituted or is mono- orpoly-substituted by hydroxy, lower alkoxy, lower alkanoyloxy, cyano,halogen, lower alkyl and/or by trifluoromethyl, the dotted line isintended to indicate the presence of a single or a double bond betweenthe carbon atoms carrying the substituents R₁ and R₂, m is 0 or 1, andin which either X is an oxygen atom or a methylene group and n is 0, orX is a direct bond and n is 1, and to their tautomers and/or salts, tothe use of these compounds, to a process for the preparation thereof,and to pharmaceutical compositions containing a compound of formula IBor a tautomer and/or a pharmaceutically acceptable salt thereof.

Amidated carboxy R₁ and R₂ has as amino group, for example, amino thatis unsubstituted or is mono- or di-substituted by lower aliphaticradicals and is, for example, carbamoyl, N-lower alkyl- or N,N-di-loweralkylcarbamoyl or N,N-lower alkylene- or N,N-(aza)-, N,N-(oxa)- orN,N-(thia)-lower alkylenecarbamoyl.

Etherified hydroxy R₂ is, for example, lower alkoxy or optionallysubstituted phenyl-lower alkoxy.

Acyl in acylated hydroxymethyl R₁ and R₂, respectively, and also inacylated hydroxy R₂ and acylated amino R₂, respectively, is, forexample, acyl derived from an organic carboxylic or sulphonic acid.

Acyl derived from an organic carboxylic acid is, for example, theradical of an aliphatic or monocyclic-aromatic carboxylic acid, such aslower alkanoyl or optionally substituted benzoyl, and also pyridoyl.

Acyl derived from an organic sulphonic acid is, for example, loweralkanesulphonyl.

The invention relates, for example, to compounds of the formula IA inwhich R₁ represents carboxy, lower alkoxycarbonyl, carbamoyl, N-loweralkylcarbamoyl or N,N-di-lower alkylcarbamoyl, R₂ represents hydrogen,an optionally etherified or acylated hydroxy group or an optionallyacylated amino group, R₃ represents hydrogen or lower alkyl, alkrepresents lower alkylene or lower alkylidene, the ring A isunsubstituted or is mono- or poly-substituted by hydroxy, lower alkoxy,lower alkanoyloxy, halogen, lower alkyl and/or by trifluoromethyl, thedotted line is intended to indicate the presence of a single or a doublebond, X represents an oxygen atom or a methylene group, Y represents anoxygen atom and n represents 1, and to their tautomers and/or salts, tothe use of these compounds, to processes for their manufacture and topharmaceutical compositions containing such a compound of the formula IAor a tautomer and/or a pharmaceutically acceptable salt thereof.

Tautomeric forms of compounds of formula I exist, for example, when R₂is hydroxy or amino and the dotted line is intended to indicate thepresence of a double bond between the carbon atoms carrying thesubstituents R₁ and R₂. The enols or enamines of formula I are then inequilibrium with the corresponding keto or ketimine tautomers,respectively, of the formula ##STR5## in which R₂ ' is oxo or imino,respectively. Representatives of both tautomeric forms can be isolated.

The compounds according to the invention can also be in the form ofstereoisomers. Since the compounds of formula I have at least one chiralcarbon atom (C-atom) (for example the C-atom carrying the radical R₃),they may be, for example, in the form of pure enantiomers orenantiomeric mixtures, such as racemates, and if there is at least onefurther chiral centre present (for example the C₄ -atom of a piperidineradical 4-substituted by R₂ other than hydrogen and/or the C₃ -atom of apiperidine radical 3-substituted by R₁ other than hydrogen), they mayalso be in the form of diastereoisomers, diastereoisomeric mixtures ormixtures of racemates. Thus, for example, geometrical isomers withrespect to R₁ and R₂, such as cis- and trans-isomers, may be formed ifR₁ and R₂ are other than hydrogen and the dotted line indicates thepresence of a single bond between the carbon atoms carrying thesubstituents R₁ and R₂.

Salts of compounds of formula I and their tautomers are especiallycorresponding acid addition salts, preferably pharmaceuticallyacceptable acid addition salts. These are formed, for example, withstrong inorganic acids, such as mineral acids, for example sulfuricacid, a phosphoric acid or a hydrohalic acid, with strong organiccarboxylic acids, such as lower alkanecarboxylic acids, for exampleacetic acid, saturated or unsaturated dicarboxylic acids, for examplemalonic, maleic or fumaric acid, or hydroxycarboxylic acids, for exampletartaric or citric acid, or with sulfonic acids, such as loweralkanesulfonic acids or unsubstituted or substituted benzenesulfonicacids, for example methane- or p-toluenesulfonic acid. If, for example,R₁ or R₂ is carboxy, corresponding compounds may form salts with bases.Suitable salts with bases are, for example, corresponding alkali metalor alkaline earth metal salts, for example sodium, potassium ormagnesium salts, pharmaceutically acceptable transition metal salts,such as zinc or copper salts, or salts with ammonia or organic amines,such as cyclic amines, mono-, di- or tri-lower alkylamines,hydroxy-lower alkylamines, for example mono-, di- or tri-hydroxy-loweralkylamines, hydroxy-lower alkyl-lower alkylamines or polyhydroxy-loweralkylamines. Cyclic amines are, for example, morpholine, thiomorpholine,piperidine or pyrrolidine. Suitable mono-lower alkylamines are, forexample, ethylamine or tert.-butylamine; suitable di-lower alkylaminesare, for example, diethylamine or diisopropylamine, and suitabletri-lower alkylamines are, for example, trimethylamine or triethylamine.Corresponding hydroxy-lower alkylamines are, for example, mono-, di- ortri-ethanolamine, and hydroxy-lower alkyl-lower alkylamines are, forexample, N,N-dimethylamino- or N,N-diethylamino-ethanol, and a suitablepolyhydroxy-lower alkylamine is, for example, glucosamine.

Also included are salts that are unsuitable for pharmaceutical uses,since they can be used, for example, for the isolation and purificationof free compounds according to the invention and their pharmaceuticallyacceptable salts.

Hereinbefore and hereinafter, unless defined otherwise, radicals orcompounds designated "lower" are to be understood as being especiallythose radicals or compounds which contain up to and including 7,especially up to and including 4, carbon atoms.

Lower alkoxy is, for example, C₁ -C₄ alkoxy, such as methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert.-butoxy.

Lower alkyl is, for example, C₁ -C₄ alkyl, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl, andalso includes C₅ -C₇ alkyl radicals, that is to say pentyl, hexyl orheptyl radicals.

Lower alkylene alk is, for example, C₁ -C₄ alkylene that bridges the tworing systems shown in formula I especially by up to and including 3carbon atoms and may be, for example, methylene, ethylene or1,3-propylene, but may also be 1,2-propylene, 1,2-or1,3-(2-methyl)propylene or 1,2- or 1,3-butylene, but it may also bridgethe two ring systems by 4 carbon atoms, that is to say it may be1,4-butylene.

Lower alkylidene alk is, for example, C₁ -C₄ alkylidene and may be, forexample, methylene, ethylidene, 1,1- or 2,2-propylidene or 1,1- or2,2-butylidene.

Lower alkanoyl is, for example, C₂ -C₅ alkanoyl, such as acetyl,propionyl, butyryl, isobutyryl or pivaloyl.

Lower alkanoyloxy is, for example, C₂ -C₅ alkanoyloxy, such as acetoxy,propionyloxy, butyryloxy, isobutyryloxy or pivaloyloxy.

Lower alkoxycarbonyl is, for example, C₂ -C₅ alkoxycarbonyl, such asmethoxy-, ethoxy-, n-propoxy-, isopropoxy, n-butoxy-, isobutoxy- ortert.-butoxy-carbonyl.

N-lower alkylcarbamoyl is, for example, N-C₁ -C₄ alkylcarbamoyl, such asN-methyl-, N-ethyl-, N-(n-propyl)-, N-isopropyl-, N-(n-butyl)-,N-isobutyl-or N-tert.-butyl-carbamoyl.

N,N-di-lower alkylcarbamoyl is, for example, N,N-di-C₁ -C₄alkylcarbamoyl in which the two N-alkyl groups may be the same ordifferent, such as N,N-dimethyl-, N,N-diethyl-, N,N-diisopropyl- orN-butyl-N-methylcarbamoyl.

N,N-lower alkylene- or N,N-(aza)-, N,N-(oxa)- or N,N-(thia)-loweralkylene-carbamoyl has, for example, from 3 up to and including 8,especially 5 or 6, ring members and is, for example, pyrrolidino-,piperidino-, piperazino-, or N'-lower alkyl-, such asN'-methyl-piperazino-, morpholino- or thiomorpholino-carbonyl.

Unsubstituted or substituted phenyl-lower alkoxy is, for example,phenyl-C₁ -C₄ alkoxy that is unsubstituted or substituted in the phenylmoiety, such as benzyloxy, p-chlorobenzyloxy, 1-phenylethoxy or1-(p-bromophenyl)-n-butoxy.

Unsubstituted or substituted benzoyl is, for example, benzoyl,p-chlorobenzoyl or p-nitrobenzoyl.

Lower alkanesulfonyl is, for example, C₁ -C₄ alkanesulfonyl, such asmethane- or ethane-sulfonyl.

Halogen is especially halogen having an atomic number of up to andincluding 35, such as fluorine, chlorine or bromine, and also includesiodine.

The compounds of formula I, their tautomers and/or theirpharmaceutically acceptable salts have, for example, valuablepharmacological, especially nootropic, properties. Thus, for example, inmice, in the Two-Compartment Passive Avoidance Test model according toMondadori and Classen, Acta Neurol. Scand. 69, Suppl. 99, 125 (1984), atdosages of approximately 0.1 mg/kg and above i.p. and p.o. they bringabout a reduction in the amnesic effect of a cerebral electric shock.

The compounds according to the invention also exhibit a considerablememory-improving action which can be detected in mice in the Step-downPassive Avoidance Test according to Mondadori and Waser,Psychopharmacol. 63, 297 (1979) at a dose of approximately 0.1 mg/kg andabove i.p. and p.o.

Accordingly, the compounds of formula I and their tautomers and/or theirpharmaceutically acceptable salts can be used as pharmaceuticals, forexample nootropics, for example for the therapeutic and/or prophylactictreatment of the symptoms of cerebral insufficiency, especially memorydisorders. The invention therefore relates also to the use of compoundsof formula I, their tautomers and/or their pharmaceutically acceptablesalts for the manufacture of medicaments, especially nootropics, for thetreatment of the symptoms of cerebral insufficiency, especially memorydisorders, which may also include the commercial formulation of theactive ingredients.

The invention relates, in appropriate consideration of theafore-mentioned proviso, especially to compounds of the formula IA inwhich either R₁ represents carboxy, lower alkoxycarbonyl, carbamoyl,N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, hydroxymethyl,lower alkanoyloxymethyl, lower alkanesulphonyloxymethyl,benzoyloxymethyl or pyridoyloxymethyl and R₂ represents hydrogen,hydroxy, lower alkoxy, benzyloxy, lower alkanoyloxy, loweralkanesulphonyloxy, benzoyloxy, pyridoyloxy, amino, lower alkanoylamino,lower alkanesulphonylamino, benzoylamino or pyridoylamino, or R₁represents hydrogen and R₂ represents carboxy, lower alkoxycarbonyl,carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl,hydroxymethyl, lower alkanoyloxymethyl, lower alkanesulphonyloxymethyl,benzoyloxymethyl or pyridoyloxymethyl, R₃ represents hydrogen or loweralkyl, alk represents lower alkylene that bridges the two ring systemsby up to and including 3 carbon atoms, or alk represents loweralkylidene, the ring A is unsubstituted or is mono-, di- orpoly-substituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen,lower alkyl and/or by trifluoromethyl, the dotted line is intended toindicate the presence of a single or a double bond, and either each of Xand Y represents an oxygen atom and n represents 1, or X represents amethylene group, Y represents an oxygen atom and n represents 1, or Xrepresents an oxygen atom, Y represents a methylene group and nrepresents 1, or X represents a direct bond, Y represents an oxygen atomand n represents 2, for example compounds of the formula IA in which R₁represents carboxy, lower alkoxycarbonyl, carbamoyl, N-loweralkylcarbamoyl or N,N-di-lower alkylcarbamoyl, R₂ represents hydrogen,hydroxy, lower alkoxy, benzyloxy, lower alkanoyloxy, loweralkanesulphonyloxy, benzoyloxy, pyridoyloxy, amino, lower alkanoylamino,benzoylamino or pyridoylamino, R₃ represents hydrogen or lower alkyl,alk represents lower alkylene that bridges the two ring systems by up toand including 3 carbon atoms, or alk represents lower alkylidene, thering A is unsubstituted or is mono-, di- or poly-substituted by hydroxy,lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or bytrifluoromethyl, the dotted line is intended to indicate the presence ofa single or a double bond, X represents an oxygen atom or a methylenegroup, Y represents an oxygen atom and n represents 1, and to theirtautomers and/or salts.

The invention relates more especially to compounds of the formula IA inwhich either R₁ represents C₁ -C₄ -alkoxycarbonyl, such as methoxy- orethoxycarbonyl, carbamoyl, hydroxymethyl or C₂ -C₅ -alkanoyloxymethyl,such as acetoxymethyl, and R₂ represents hydrogen or hydroxy, or R₁represents hydrogen and R₂ represents C₁ -C₄ -alkoxycarbonyl, such asethoxycarbonyl, R₃ represents hydrogen or C₁ -C₄ -alkyl, such as methyl,alk represents C₁ -C₄ -alkylene that bridges the two ring systems by upto and including 3 carbon atoms, such as methylene or ethylene, the ringA is unsubstituted or is substituted, especially in the 7-position, byC₁ -C₄ -alkoxy, such as methoxy, the dotted line is intended to indicatethe presence of a single or a double bond, and either each of X and Yrepresents an oxygen atom and n represents 1, or X represents amethylene group, Y represents an oxygen atom and n represents 1, or Xrepresents an oxygen atom, Y represents a methylene group and nrepresents 1, or X represents a direct bond, Y represents an oxygen atomand n represents 2, for example compounds of the formula IA in which R₁represents C₁ -C₄ -alkoxycarbonyl, such as methoxycarbonyl, R₂represents hydrogen or hydroxy, R₃ represents hydrogen or C₁ -C₄ -alkyl,such as methyl, alk represents C₁ -C₄ -alkylene that bridges the tworing systems by up to and including 3 carbon atoms, such as methylene orethylene, the ring A is unsubstituted, the dotted line is intended toindicate the presence of a single or a double bond, X represents anoxygen atom or a methylene group, Y represents an oxygen atom and nrepresents 1, and to their tautomers and/or salts.

The invention relates especially to compounds of the formula IA in whichR₁ represents C₁ -C₄ -alkoxycarbonyl, such as methoxy- orethoxy-carbonyl, R₂ represents hydrogen or hydroxy, R₃ representshydrogen, alk represents methylene or ethylene, the ring A isunsubstituted, the dotted line is intended to indicate the presence of asingle or a double bond, X represents an oxygen atom or a methylenegroup, Y represents an oxygen atom and n represents 1, and to theirtautomers and/or salts.

The invention relates most especially to compounds of the formula IA inwhich R₁ represents C₁ -C₄ -alkoxycarbonyl, such as methoxycarbonyl, R₂represents hydrogen, R₃ represents hydrogen, alk represents methylene orethylene, the ring A is unsubstituted, the dotted line is intended toindicate the presence of a single or a double bond, X represents anoxygen atom or a methylene group, Y represents an oxygen atom and nrepresents 1, or in which R₁ represents C₁ -C₄ -alkoxycarbonyl, such asmethoxycarbonyl, R₂ represents hydroxy, R₃ represents hydrogen, alkrepresents methylene, the ring A is unsubstituted, the dotted line isintended to indicate the presence of a double bond, X represents anoxygen atom or a methylene group, Y represents an oxygen atom and nrepresents 1, and in each case to their tautomers and/or salts.

The invention relates especially to compounds of formula IB in whicheither R₁ is carboxy, lower alkoxycarbonyl, carbamoyl, N-loweralkylcarbamoyl, N,N-di-lower alkylcarbamoyl, N,N-loweralkylenecarbamoyl, N,N-(aza)-, N,N-(oxa)- or N,N-(thia)-loweralkylenecarbamoyl, hydroxymethyl, lower alkanoyloxymethyl, loweralkanesulfonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl and R₂ ishydrogen, hydroxy, lower alkoxy, benzyloxy, lower alkanoyloxy, loweralkanesulfonyloxy, benzoyloxy, pyridoyloxy, amino, lower alkanoylamino,lower alkanesulfonylamino, benzoylamino or pyridoylamino, or R₁ ishydrogen and R₂ is carboxy, lower alkoxycarbonyl, carbamoyl, N-loweralkylcarbamoyl, N,N-di-lower alkylcarbamoyl, N,N-loweralkylenecarbamoyl, N,N-(aza)-, N,N-(oxa)- or N,N-(thia)-loweralkylenecarbamoyl, hydroxymethyl, lower alkanoyloxymethyl, loweralkanesulfonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl, and inwhich R₃ is hydrogen or lower alkyl, R₄ is lower alkyl, R₅ is loweralkyl, alk is lower alkylene that bridges the two ring systems shown informula IB by up to and including 3 carbon atoms or is lower alkylidene,the ring A is unsubstituted or is mono-, di- or poly-substituted byhydroxy, lower alkoxy, lower alkanoyloxy, cyano, halogen, lower alkyland/or by trifluoromethyl, the dotted line is intended to indicate thepresence of a single or a double bond between the carbon atoms carryingthe substituents R₁ and R₂, m is 0 or 1, and in which either X is anoxygen atom or a methylene group and n is 0, or X is a direct bond and nis 1, and their tautomers and/or salts.

The invention relates more especially to compounds of formula IB inwhich R₁ is C₁ -C₄ alkoxycarbonyl, such as methoxy- or ethoxy-carbonyl,or carbamoyl, R₂ is hydrogen or hydroxy, R₃ is hydrogen, R₄ is C₁ -C₄alkyl, such as methyl, R₅ is C₁ -C₄ alkyl, such as methyl, alk is C₁ -C₄alkylene that bridges the two ring systems shown in formula IB by up toand including 3 carbon atoms, such as methylene or ethylene, the ring Ais unsubstituted or is substituted, especially in the 6-position, by C₁-C₄ alkoxy, such as methoxy, C₁ -C₄ alkyl, such as methyl, halogenhaving an atomic number of up to and including 35, such as fluorine orchlorine, cyano or by trifluoromethyl, the dotted line is intended toindicate the presence of a single or a double bond between the carbonatoms carrying the substituents R₁ and R₂, m is 1, X is an oxygen atomor a methylene group and n is 0, and their tautomers and/or salts.

The invention relates especially to compounds of formula IB in which R₁is C₁ -C₄ alkoxycarbonyl, such as methoxycarbonyl, R₂ is hydrogen, R₃ ishydrogen, R₄ is C₁ -C₄ alkyl, such as methyl, R₅ is C₁ -C₄ alkyl, suchas methyl, alk is ethylene, the ring A is unsubstituted or ismono-substituted, especially in the 6-position, by halogen having anatomic number of up to and including 35, such as fluorine or chlorine,the dotted line is intended to indicate the presence of a double bondbetween the carbon atoms carrying the substituents R₁ and R₂, m is 1, Xis a methylene group and n is 0, and their salts.

The invention relates more especially to compounds of formula IB inwhich R₁ is C₁ -C₄ alkoxycarbonyl, such as methoxycarbonyl, R₂ ishydrogen, R₃ is hydrogen, R₄ is C₁ -C₄ alkyl, such as methyl, R₅ is C₁-C₄ alkyl, such as methyl, alk is ethylene, the ring A is unsubstituted,the dotted line is intended to indicate the presence of a double bondbetween the carbon atoms carrying the substituents R₁ and R₂, m is 1, Xis a methylene group and n is 0, and their salts.

The invention relates specifically to the novel compounds of formula Imentioned in the Examples and their salts and to process for theirpreparation.

The present invention relates also to a process for the preparation ofcompounds of formula I or their tautomers and/or salts, in whichprocess, for example,

a) a compound of formula ##STR6## or a salt thereof, in which X₁ ishydroxy or reactive esterified hydroxy, is reacted with a compound offormula ##STR7## or with a tautomer and/or salt thereof, or

b) in a compound of formula ##STR8## or in a tautomer and/or saltthereof, in which X₂ is a radical that can be converted into R₁ otherthan hydrogen and X₅ is a radical R_(a), and R_(a) is hydrogen, a free,etherified or acylated hydroxy group or a free or acylated amino group,X₂ is converted into R₁ other than hydrogen, or in a compound of formulaIII or in a tautomer and/or salt thereof, in which X₂ is hydrogen and X₅is a radical that can be converted into R_(b), and R_(b) is a radical R₂other than a radical R_(a), X₅ is converted into R_(b), or

c) for the preparation of a compound of formula I or a tautomer and/orsalt thereof, in which R₂ is hydroxy or amino and in which R₁ is otherthan hydrogen and other than free or acylated hydroxymethyl, a compoundof formula ##STR9## in which Y₁ is a group of formula --CH═R₂ ',--C(Y₂)═R₂ ' or --CH(Y₂)--R₂ or cyano, wherein R₂ ' is oxo or imino andY₂ is a removable radical, or a salt thereof is cyclised, or

d) for the preparation of a compound of formula I', in which R₂ ' is oxoor imino and R₁ is other than hydrogen, or a tautomer and/or saltthereof, a compound of formula ##STR10## or a tautomer and/or a saltthereof is reacted with a compound of formula

    X.sub.3 --R.sub.1                                          (Vb)

or with a salt thereof, in which R₁ is other than hydrogen and X₃ ishalogen or lower alkoxy, or

e) for the preparation of a compound of formula I or a tautomer and/orsalt thereof, in which R₂ is a free, etherified or acylated hydroxygroup or a free or acylated amino group, in a compound of formula##STR11## or in a salt thereof, in which X₄ is a radical that can beconverted into R₂, X₄ is converted into R₂, or

f) in a salt of formula ##STR12## in which A.sup.⊖ is the anion of anacid, R₁ " is a radical R₁ or etherified or protected hydroxymethyl, andR₂ " is a radical R₂, protected hydroxy, protected amino or etherifiedor protected hydroxymethyl, the excess double bonds are reduced tosingle bonds and, if R₁ " is other than R₁ and/or R₂ " is other than R₂,R₁ " is converted into R₁ and/or R₂ " is converted into R₂, or

g) for the preparation of a compound of formula I or a tautomer and/orsalt thereof, in which R₂ is carboxy, amidated carboxy or loweralkoxycarbonyl and the dotted line is intended to indicate the presenceof a single bond between the carbon atoms carrying the substituents R₁and R₂, a compound of formula ##STR13## in which Y₂ is a removableradical, or a salt thereof is cyclised, and, in the case of each ofprocess variants a) to g), a protecting group which may be present isremoved, and, if desired, a compound of formula I obtainable inaccordance with the process or by other means is converted into adifferent compound of formula I, an isomeric mixture obtainable inaccordance with the process is separated into the components, anenantiomeric or diastereoisomeric mixture obtainable in accordance withthe process is separated into the enantiomers or diastereoisomers,respectively, and/or a free compound of formula I obtainable inaccordance with the process is converted into a salt or a saltobtainable in accordance with the process is converted into the freecompound of formula I or into a different salt.

The reactions described in the variants hereinbefore and hereinafter arecarried out in a manner known per se, for example in the absence or,customarily, in the presence of a suitable solvent or diluent or amixture thereof, the reactions being carried out, as necessary, withcooling, at room temperature or with heating, for example in atemperature range of from approximately -10° C. to the boilingtemperature of the reaction medium, preferably at from approximately 20°C. to approximately 150° C., and, if necessary, in a closed vessel,under pressure, in an inert gas atmosphere and/or under anhydrousconditions.

The starting materials of formulae IIa and IIb, III, IV, Va and Vb, VI,VII and VIII, which are mentioned hereinbefore and hereinafter and whichwere developed for the preparation of the compounds of formula I, theirtautomers and/or salts, are known in some cases or they can likewise beprepared according to methods known per se, for example analogously tothe process variants described above.

Starting materials having basic centres may, for example, be in the formof acid addition salts, for example with the acids listed above, whilststarting compounds having acidic groups may form salts with bases, forexample of the kind mentioned above. Starting compounds may also be inthe form of tautomers, especially in the case of compounds of formulaIIb when R₂ is hydroxy and the dotted line is intended to indicate thepresence of a double bond between the carbon atoms carrying thesubstituents R₁ and R₂.

Variant a)

Reactive esterified hydroxy is especially hydroxy esterified by a stronginorganic acid or organic sulfonic acid, for example halogen, such aschlorine, bromine or iodine, sulfonyloxy, such as hydroxysulfonyloxy,halosulfonyloxy, for example fluorosulfonyloxy, lower alkanesulfonyloxythat is unsubstituted or substituted, for example, by halogen, forexample methane- or trifluoromethane-sulfonyloxy,cycloalkanesulfonyloxy, for example cyclohexanesulfonyloxy, orbenzenesulfonyloxy that is unsubstituted or substituted, for example, bylower alkyl or by halogen, for example p-bromophenyl- orp-toluene-sulfonyloxy.

The N-alkylation is carried out especially in the presence of acondensation agent, such as a suitable base. Suitable bases are, forexample, alkali metal hydroxides, hydrides, amides, alkanolates,carbonates, triphenylmethylides, di-lower alkylamides, amino-loweralkylamides or lower alkylsilylamides, or naphthaleneamines, loweralkylamines, basic heterocycles, ammonium hydroxides and carbocyclicamines. There may be mentioned by way of example: sodium hydroxide,hydride, amide or ethanolate, potassium tert.-butanolate or carbonate,lithium triphenylmethylide, lithium diisopropylamide, potassium3-(aminopropyl)-amide or bis-(trimethylsilyl)-amide, ordimethylaminonaphthalene, di- or triethylamine, pyridine,benzyltrimethylammonium hydroxide, 1,5-diazabicyclo[4.3.0]non-5-ene(DBN) and 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU).

The starting materials of formulae IIa and IIb are either known or theycan be prepared analogously to the known starting materials.

Variant b)

A radical X₂ that can be converted into R₁ other than hydrogen, or aradical X₅ that can be converted into a radical R_(b) is, for example,functionally modified carboxy other than R₁ or R_(b), respectively, suchas cyano, anhydridised carboxy, unsubstituted or substituted amidino,free, esterified or anhydridised carboximidoyl, esterified or amidatedcarboxy other than esterified or amidated carboxy R₁ or R₂, tri-loweralkoxy- or tri-halo-methyl.

Anhydridised carboxy is, for example, carboxy anhydridised with amineral acid, such as a hydrohalic acid, or with a carboxylic acid, suchas an unsubstituted or substituted lower alkanoic or benzoic acid, orwith a carbonic acid halide lower alkyl semiester. Examples that may bementioned are halocarbonyl, such as chlorocarbonyl, loweralkanoyloxycarbonyl, such as acetoxycarbonyl, or loweralkoxycarbonyloxycarbonyl, such as ethoxycarbonyloxycarbonyl.

Substituted amidino is, for example, amidino substituted by an aliphaticradical, for example lower alkyl, such as lower alkylamidino, forexample ethylamidino.

Esterified or anhydridised carboximidoyl is to be understood as being,for example, alkoxy- or halo-carboximidoyl, for example lower alkoxy-,such as ethoxy-, or chlorocarboximidoyl, respectively.

Tri-lower alkoxymethyl or tri-halomethyl is, for example,trimethoxymethyl or trichloromethyl, respectively.

Radicals R_(b) are, for example, carboxy, lower alkoxycarbonyl, amidatedcarboxy or free or acylated hydroxymethyl radicals R₂.

X₂ can be converted into R₁ other than hydrogen, for example, bysolvolysis, just as X₅ can be converted into a radical R_(b), forexample, by solvolysis. Solvolysis agents are, for example, water, loweralkanols corresponding to the desired esterified carboxy R₁ and R₂,ammonia, or amines corresponding to the desired amidated carboxy groupR₁ and R₂. The treatment with a corresponding solvolysis agent is ifappropriate carried out in the presence of an acid or base. Suitableacids are, for example, inorganic or organic protonic acids, such asmineral acids, for example sulfuric acid or a hydrohalic acid, forexample hydrochloric acid, sulfonic acids, for example loweralkanesulfonic acids or unsubstituted or substituted benzenesulfonicacids, for example methane- or p-toluenesulfonic acid, or carboxylicacids, for example lower alkanecarboxylic acids, for example aceticacid, whilst bases that may be used are, for example, those mentionedunder Variant a), especially sodium or potassium hydroxide.

In the solvolysis, the cyano group, anhydridised carboxy, unsubstitutedor substituted amidino, free, esterified or anhydridised carboximidoyl,esterified or amidated carboxy other than esterified or amidated carboxyR₁ and R₂, tri-lower alkoxymethyl or trihalomethyl is hydrolysed tocarboxy. Lower alkanoyloxy radicals which may be present at ring A mayalso be hydrolysed to hydroxy in the course of the hydrolysis.

Cyano, anhydridised carboxy, and esterified or amidated carboxy otherthan esterified or amidated carboxy R₁ and R₂ are alcoholysed, forexample with a suitable lower alkanol, to esterified carboxy R₁ and R₂,and cyano and anhydridised carboxy are ammonolysed or aminolysed, forexample, with ammonia or with an amine corresponding to the amidatedcarboxy R₁ and R₂, respectively.

The starting material of formula III can be prepared, for example, in amanner analogous to that described under Variant a) by reacting acompound of formula ##STR14## with a compound of formula ##STR15## orwith a tautomer and/or salt thereof, in the presence of one of thementioned bases.

Compounds of formula III in which X₂ is a radical that can be convertedinto R₁ other than hydrogen and X₅ is hydroxy or amino, canadvantageously be prepared also by cyclisation of a compound of formula##STR16## in which Y₁ is a group of formula --CH═R₂ ', --C(Y₂)═R₂ ',--CH(Y₂)--R₂ or cyano, wherein R₂ ' is oxo or imino, R₂ is hydroxy oramino and Y₂ is a removable radical, or a salt thereof, the operationbeing carried out, for example, in a manner analogous to that givenunder Process Variant c).

Variant c)

Removable radicals Y₂ in groups of formula --C(Y₂)═R₂ ' or --CH(Y₂)--R₂are, for example, reactive esterified hydroxy groups, such as hydroxyesterified by a strong inorganic acid or organic sulfonic acid, forexample halogen, such as chlorine, bromine or iodine, sulfonyloxy, suchas hydroxysulfonyloxy, halosulfonyloxy, for example fluorosulfonyloxy,lower alkanesulfonyloxy that is unsubstituted or substituted, forexample, by halogen, for example methane- ortrifluoromethane-sulfonyloxy, cycloalkanesulfonyloxy, for examplecyclohexanesulfonyloxy, or benzenesulfonyloxy that is unsubstituted orsubstituted, for example, by lower alkyl or by halogen, for examplep-bromophenyl- or p-toluene-sulfonyloxy, or etherified hydroxy groups,for example lower alkoxy or unsubstituted or substituted phenyl-loweralkoxy.

The cyclisation can be carried out, for example, analogously to theDieckmann reaction, especially in the presence of one of the basesmentioned under Variant a), and with subsequent working up by means ofhydrolysis.

In a preferred form of the process, for example a compound of formula##STR17## in which R₂ ' is oxo or imino, can be subjected to treatmentwith one of the mentioned bases, especially with an alkali metal loweralkanolate, for example with sodium methanolate or sodium ethanolate.During this treatment, the compound IVa cyclises to form a compound offormula I in which the dotted line indicates the presence of a singlebond between the carbon atoms carrying the substituents R₁ and R₂, andR₂ is hydroxy or amino. Starting materials of formula IVa are obtained,for example, by reacting a reactive alkyl ester of formula ##STR18## inwhich X₁ is reactive esterified hydroxy, with a compound of formula H₂N--CH₂ --CH₂ --R₁ (IVb) and reacting the resulting intermediate offormula ##STR19## with acrolein or with a free or functionally modifiedaldehyde of formula Y₁ --CH₂ --CH₂ --CH═R₂ ' (IVd; Y₁ =reactiveesterified hydroxy; R₂ '=oxo or imino).

In another preferred form of VAriant c), a compound of formula IV inwhich Y₁ and R₁ are lower alkoxycarbonyl, that is to say in which Y₁ isa group of formula --C(Y₂)═R₂ ' wherein R₂ ' is oxo and the removableradical Y₂ has a lower alkoxy group as etherified hydroxy, is cyclisedto form the corresponding compound of formula I' in which R₂ ' is oxoand R₁ is lower alkoxycarbonyl.

For the preparation of the last-mentioned starting compounds of formulaIV it is possible to use as starting materials, for example, compoundsof formula ##STR20## or salts thereof, which are obtainable, forexample, by reduction of the corresponding nitriles, and to react themwith at least 2 mols of a compound of formula ##STR21##

Variant d)

The C-acylation in accordance with the process can be effectedespecially in the presence of one of the bases mentioned under Varianta), but especially advantageously by means of a metal base, such aslithium diisopropylamine or n-butyllithium, optionally in the presenceof chlorotrimethylsilane.

The reaction of a compound of formula ##STR22## with a compound offormula ##STR23## or with a salt thereof, analogously to theN-alkylation according to Variant a) in the presence of one of the basesmentioned, results in the starting material of formula Va.

Variant e)

Radicals X₄ that can be converted into free, etherified or acylatedhydroxy or free or acylated amino R₂ are, for example, radicals that canbe converted into such a group R₂ by solvolysis, that is to say byreaction with a corresponding compound of formula R₂ H or with a saltthereof, for example halogen atoms, for example chlorine, bromine oriodine. Radicals X₄ that can be converted into hydroxy R₂ are alsodiazonium groups, for example of formula --N₂.sup.⊕ A.sup.⊖ in whichA.sup.⊖ is the anion of a strong acid, such as a mineral acid, forexample the chloride or sulfate ion.

The solvolysis is effected in customary manner, for example in thepresence of a base, such as an alkali metal or alkaline earth metalhydroxide, for example sodium or potassium hydroxide, or a tertiarynitrogen base, for example a tri-lower alkylamine, such astriethylamine, or a heteroaromatic nitrogen base, such as pyridine, or aquaternary ammonium hydroxide, such as benzyltrimethylammoniumhydroxide, or by using the compound R₂ H in the form of a metal salt,for example of formula R₂.sup.⊖ M.sup.⊕ in which M.sup.⊕ is an alkalimetal cation, such as the sodium ion. The operation is advantageouslycarried out in the presence of a solvent or diluent, for example in anexcess of the reactant R₂ H and/or in an inert solvent that is misciblewith the latter, if necessary with cooling or heating, for example in atemperature range of approximately from 0° to 120° C., and/or underinert gas, such as nitrogen.

The solvolysis of radicals X₄ to free, etherified or acylated hydroxy orfree or acylated amino R₂ can optionally be combined with the solvolyticconversion of solvolysable groups R₁ into other groups R₁ according tothe invention; for example, in the ammonolysis of radicals X₄ to aminoR₂, lower alkoxycarbonyl groups R₁ or other groups R₁ that can besolvolysed to carbamoyl R₁ can, if desired, be ammonolysed to formcarbamoyl groups R₁ at the same time.

For the manufacture of starting compounds of formula VI and the saltsthereof, for example compounds of formula IIa ##STR24## are used asstarting materials and are reacted with a corresponding compound offormula ##STR25## or a salt thereof, in the presence of one of the basesmentioned above, the operation being carried out, for example, in amanner analogous to that described under Process Variant a).

In a preferred form of the process, compounds of formula VI in which X₄is halogen and the dotted line indicates the presence of a single bondbetween the carbon atoms carrying the substituents R₁ and X₄ and saltsthereof are obtained by reacting a compound of formula I in which R₂ ishydroxy and the dotted line indicates the presence of a single bondbetween the carbon atoms carrying the substituents R₁ and R₂, or a saltthereof, with a halogenating agent, such as phosphorus trichloride orpentachloride or thionyl chloride, it being possible to obtain thecorresponding compounds of formula I and their salts, for example, in amanner analogous to that described under Process Variant a) or c).

Variant f)

The anion A.sup.⊖ is, for example, the anion of a strong protonic acid,for example a halide ion, such as a chloride, bromide or iodide ion, ora sulfonate ion, such as an unsubstituted or substituted lower alkane-or benzene-sulfonate ion, for example the methanesulfonate,ethanesulfonate or p-bromophenylsulfonate or p-toluenesulfonate ion.Protected hydroxy is, for example, silyloxy, such as tri-loweralkylsilyloxy, for example trimethylsilyloxy, but may also betriphenyl-lower alkoxy, for example trityloxy. Protected amino is, forexample, silylamino, such as tri-lower alkylsilylamino, for exampletrimethylsilylamino, but may also be phenyl-, diphenyl- ortriphenyl-lower alkylamino, such as benzylamino, diphenylmethylamino ortritylamino. Etherified hydroxymethyl is, for example, loweralkoxymethyl, such as methoxy- or ethoxy-methyl, or unsubstituted orsubstituted phenyl-lower alkoxymethyl, for example phenyl-C₁ -C₄alkoxymethyl substituted in the phenyl moiety, such as benzyloxy-,p-chlorobenzyloxy-, 1-phenylethoxy- or 1-(p-bromophenyl)-n-butoxymethyl.Protected hydroxymethyl is, for example, silyloxymethyl, such astri-lower alkylsilyloxy-, for example trimethylsilyloxy-methyl, but mayalso be triphenyl-lower alkoxy-, for example trityloxy-methyl.

The process variant f) is especially suitable for the preparation of acompound of formula I or a tautomer and/or salt thereof, in which eitherR₁ is carboxy, lower alkoxycarbonyl, amidated carboxy or hydroxymethyland R₂ is hydrogen, hydroxy or amino, or R₁ is hydrogen and R₂ iscarboxy, lower alkoxycarbonyl, amidated carboxy or hydroxymethyl.

The reduction of the excess double bonds is effected by treatment with asuitable reducing agent, for example by hydrogenation in the presence ofa hydrogenation catalyst, by reduction with a hydride-transfer reagentor by reduction with a metallic reduction system consisting of metal anda proton-removing agent.

Hydrogenation catalysts that come into consideration are, for example,elements of sub-group VIII of the Periodic Table of Elements orderivatives thereof, such as palladium, platinum, platinum oxide,ruthenium, rhodium, tris(triphenylphosphane)rhodium(I) halide, forexample the chloride, or Raney nickel, which are optionally supported ona carrier, such as activated carbon, an alkali metal carbonate orsulfate, or a silica gel. Suitable hydride-transfer reagents are, forexample, suitable light metal hydrides, especially alkali metalaluminium hydrides or borohydrides, such as lithium aluminium hydride,lithium triethylborohydride, sodium borohydride, sodiumcyanoborohydride, or tin hydrides, such as triethyl- or tributyl-tinhydride, or diborane. The metal component of the metallic reductionsystem is, for example, a base metal, such as an alkali metal oralkaline earth metal, for example lithium, sodium, potassium, magnesiumor calcium, or a transition metal, for example zinc, tin, iron ortitanium, whilst suitable proton-removing agents are, for example,protonic acids of the kind mentioned above, such as hydrochloric oracetic acid, lower alkanols, such as ethanol, and/or amines or ammonia.Such systems are, for example, sodium/ammonia, zinc/hydrochloric acid,zinc/acetic acid or zinc/ethanol.

If R₁ " is other than R₁ and/or R₂ " is other than R₂, the conversion ofR₁ " into R₁ and/or R₂ " into R₂, that is to say the removal of theprotecting groups, i.e. the freeing of the corresponding radicals R₁and/or R₂, is effected in the same or in a subsequent reaction step, theoperation being carried out in the usual way, for example in the mannerdescribed following process variant g).

The preparation of starting compounds of formula VII is effected, forexample, by reacting compounds of formula ##STR26## in which X₁ isreactive esterified hydroxy corresponding in its single negativelycharged form to the anion A⁶³ , with compounds of formula ##STR27## orwith a salt thereof, the operation being carried out, for example, in amanner analogous to that described under Process Variant a).

Variant g)

Removable radicals Y₂ in compounds VIII are, for example, reactiveesterified hydroxy groups, such as hydroxy esterified by a stronginorganic acid or organic sulfonic acid, for example halogen, such aschlorine, bromine or iodine, sulfonyloxy, such as hydroxysulfonyloxy,halosulfonyloxy, for example fluorosulfonyloxy, lower alkanesulfonyloxythat is unsubstituted or substituted, for example, by halogen, forexample methane- or trifluoromethanesulfonyloxy, cycloalkanesulfonyloxy,for example cyclohexanesulfonyloxy, or benzenesulfonyloxy that isunsubstituted or substituted, for example, by lower alkyl or by halogen,for example p-bromophenyl- or p-toluene-sulfonyloxy, or etherifiedhydroxy groups, for example lower alkoxy or unsubstituted or substitutedphenyl-lower alkoxy.

The cyclisation can be carried out, for example, in the presence of oneof the bases mentioned under Variant a), especially in the presence ofan alkali metal lower alkanolate, for example with sodium methanolate orethanolate.

The starting materials VIII are obtained, for example, by reacting acompound of formula ##STR28## or a salt thereof with a compound offormula Y₂ --CH₂ --CH(Y₂)--R₁ (IVi).

In the starting materials of formulae IIb, III, IIIa, IV, IVg, VII andVIIa, a hydroxy group R₂ may be in etherified form and a hydroxy oramino group R₂ may also be in intermediately protected form, just as ahydroxymethyl group R₁ or R₂ in compounds IIb, IVi, Vb, VI, VIa, VII,VIIa and VIII may be in etherified or intermediately protected form.Protected hydroxy is, for example, silyloxy, such as tri-loweralkylsilyloxy, for example trimethylsilyloxy, but may also betriphenyl-lower alkoxy, for example trityloxy. Protected amino is, forexample, silylamino, such as tri-lower alkylsilylamino, for exampletrimethylsilylamino, but may also be phenyl-, diphenyl- ortriphenyl-lower alkylamino, such as benzylamino, diphenylmethylamino ortritylamino. Etherified hydroxymethyl is, for example, loweralkoxymethyl, such as methoxy- or ethoxy-methyl, or unsubstituted orsubstituted phenyl-lower alkoxymethyl, for example phenyl-C₁ -C₄alkoxymethyl substituted in the phenyl moiety, such as benzyloxy-,p-chlorobenzyloxy-, 1-phenylethoxy- or1-(p-bromophenyl)-n-butoxy-methyl. Protected hydroxymethyl is, forexample, silyloxymethyl, such as tri-lower alkylsilyloxy-, for exampletrimethylsilyloxy-methyl, but may also be triphenyl-lower alkoxy-, forexample trityloxy-methyl.

The freeing of etherified and intermediately protected, respectively,radicals R₁ and R₂, that is to say the removal of the intermediateprotecting groups, is effected in customary manner, for example bysolvolysis, such as mild hydrolysis, for example treatment with waterunder neutral or weakly acidic conditions, for example by the action ofdilute aqueous mineral or carboxylic acids, for example dilutehydrochloric or acetic acid. The freeing of intermediately protectedhydroxy and amino groups R₂ " and of etherified or protectedhydroxymethyl groups R₁ 41 R in starting materials of formulae VII andVIIa is effected in analogous manner.

Compounds of formula I obtainable according to the process or by othermeans can be converted in customary manner into other compounds offormula I.

For example, esterified or amidated carboxy groups R₁ and R₂ can behydrolysed to carboxy R₁ and R₂ in customary manner, for example in thepresence of a basic or acidic hydrolysis agent, such as an alkali metalhydroxide or carbonate, for example sodium hydroxide or potassiumcarbonate, or a mineral acid, for example hydrochloric acid or sulfuricacid. Esterified carboxy groups R₁ and R₂ can also be converted intoother esterified carboxy groups R₁ and R₂ by transesterification, thatis to say treatment with an alcohol in the presence of an acidic orbasic solvolysis agent, such as a mineral acid, for example sulfuricacid, or a corresponding alkali metal alcoholate or an alkali metalhydroxide, or converted into amidated carboxy R₁ and R₂ by reaction withammonia or with a corresponding amine having at least one hydrogen atom.

Free carboxy R₁ and R₂ can be converted into esterified carboxy R₁ andR₂ in customary manner, for example by treatment with a correspondingalcohol in the presence of a mineral acid, for example sulfuric acid, orby conversion into a halide and subsequent reaction with a correspondingalcohol, for example in the presence of pyridine or triethylamine, or byconversion into an alkali metal salt and subsequent reaction with areactive ester of the corresponding alcohol, such as a correspondinghalide. Likewise, a carboxy compound can be esterified with acorresponding alcohol using a dehydrating agent, such asN,N'-dicyclohexylcarbodiimide. Free or esterified carboxy R₁ and R₂ canalso be converted into amidated carboxy R₁ and R₂ by reaction withammonia or an amine having at least one hydrogen atom and dehydration ofthe intermediately formed ammonium salt, for example by heating or bymeans of a dehydrating agent, such as N,N'-dicyclohexylcarbodiimide, orby conversion into the halide and subsequent reaction with ammonia orwith an amine having at least one hydrogen atom.

Furthermore, hydroxy groups which may be present can be esterified, forexample converted by treatment with a lower alkanecarboxylic acidanhydride or halide into lower alkanoyloxy, or converted by reactionwith a reactive ester, especially a hydrobromic or hydrochloric acidester, of a lower alkanol into corresponding etherified hydroxy.Conversely, the hydroxy group may be freed from esterified or etherifiedhydroxy, such as lower alkanoyloxy or lower alkoxy, by solvolysis,preferably under acidic conditions. In an analogous manner, it is alsopossible to hydrolyse etherified or acylated hydroxy R₂ to hydroxy.

In corresponding manner, furthermore hydroxymethyl R₁ and R₂ can beesterified, for example converted by treatment with a loweralkanecarboxylic acid anhydride or halide into lower alkanoyloxymethylR₁ and R₂. Conversely, the hydroxy group may be freed from acylatedhydroxymethyl R₁ and R₂, for example lower alkanoyloxymethyl, bysolvolysis, preferably under acidic conditions.

Furthermore, hydroxymethyl R₁ and R₂ can be converted in customarymanner into lower alkoxycarbonyl or amidated carboxy R₁ and R₂, theoperation being carried out, for example, by first oxidisinghydroxymethyl R₁ and R₂ to carboxy in customary manner, for example inthe presence of an oxidising agent, such as potassium permanganate orpotassium dichromate, and then converting the carboxy group into loweralkoxycarbonyl R₁ and R₂ in customary manner, for example by treatmentwith a corresponding alcohol in the presence of a mineral acid, forexample sulfuric acid, or by conversion into a halide and subsequentreaction with a corresponding alcohol, for example in the presence ofpyridine or triethylamine, or by conversion into an alkali metal saltand subsequent reaction with a reactive ester of the correspondingalcohol, such as a corresponding halide, or by using a dehydratingagent, such as N,N'-dicyclohexylcarbodiimide, with a correspondingalcohol, or converting the carboxy group into amidated carboxy R₁ and R₂by reaction with ammonia or an amine having at least one hydrogen atomand dehydration of the intermediately formed ammonium salt, for exampleby heating or by means of a dehydrating agent, such asN,N'-dicyclohexylcarbodiimide, or by conversion into the halide andsubsequent reaction with ammonia or with an amine having at least onehydrogen atom. It is also possible to convert acylated hydroxymethyl R₁and R₂ into esterified or amidated carboxy R₁ and R₂ by first freeingthe acylated hydroxymethyl group by solvolysis, for example in themanner described above, and then converting the resulting freehydroxymethyl group, in the manner described above, into a carboxy groupand converting the latter further into an esterified or amidated carboxygroup. Conversely, esterified or amidated carboxy groups R₁ and R₂ canbe converted into free or acylated hydroxymethyl R₁ and R₂ by firsthydrolysing the esterified or amidated carboxy group R₁ and R₂ tocarboxy in customary manner, for example in the presence of a basic oracidic hydrolysis agent, such as an alkali metal hydroxide or carbonate,for example sodium hydroxide or potassium carbonate, or a mineral acid,for example hydrochloric acid or sulfuric acid, and then reducing theresulting carboxy group in customary manner, for example in the presenceof a reducing agent, for example of the kind mentioned above, tohydroxymethyl R₁ and R₂ and then, if desired, converting the latter intoacylated hydroxymethyl R₁ and R₂, for example in the manner describedabove.

In compounds of formula I in which the dotted line indicates thepresence of a double bond between the carbon atoms carrying thesubstituents R₁ and R₂, that bond can be hydrogenated to a single bond,for example in a manner known per se using a reducing agent, for exampleof the kind mentioned under Variant f).

Furthermore, a compound of formula I in which the dotted line indicatesthe presence of a double bond between the carbon atoms carrying thesubstituents R₁ and R₂ and R₂ is hydrogen, can be converted into acorresponding piperidine compound, for example in a manner known per seby the addition of a compound R₂ --H in which R₂ is a free, etherifiedor acylated hydroxy group or a free or acylated amino group. Theaddition is carried out especially in the presence of a suitable base,for example of the kind mentioned under Variant a).

Conversely, compounds of formula I in which the dotted line indicatesthe presence of a single bond between the carbon atoms carrying thesubstituents R₁ and R₂ can be converted in a manner known per se intocorresponding tetrahydropyridine compounds in which R₂ is hydrogen, forexample by elimination of a compound R₂ --H in which R₂ is a free,etherified or acylated hydroxy group or a free or acylated amino group.Leaving groups R₂ that are less suitable for elimination, for examplehydroxy, can first be converted, for example in situ, into more suitableleaving groups R₂, for example lower alkanesulfonyloxy, such asmethanesulfonyloxy, or halogen, such as chlorine, bromine or iodine. Theelimination is effected especially in the presence of a suitable base,for example of the kind mentioned under Variant a).

Salts of compounds of formula I and of their tautomers can be producedin a manner known per se. Thus, for example, acid addition salts ofcompounds of formula I are obtained by treatment with an acid or asuitable ion exchange reagent. Salts can be converted into the freecompounds of formula I in customary manner; for example acid additionsalts can be converted by treatment with a suitable basic agent.

Depending upon the procedure and reaction conditions, the compounds offormula I having salt-forming, especially basic, properties may beobtained in free form or in the form of salts.

As a result of the close relationship between the novel compound offormula I in free form and in the form of its salts, hereinbefore andhereinafter the free compound of formula I or its salts should beunderstood as meaning also the corresponding salts or the free compoundof formula I, respectively, where appropriate and expedient.

The novel compounds of formula I, including salts of salt-formingcompounds, can also be obtained in the form of their hydrates or mayinclude other solvents, for example those used for the crystallisationof compounds in solid form.

Depending upon the starting materials and procedures chosen, the novelcompounds of formula I may be in the form of one of the possible isomersor in the form of a mixture thereof. Depending upon the molecularsymmetry, for example depending upon the number and the absolute andrelative configuration of the chiral centres, such as asymmetric carbonatoms, as pure isomers there may be obtained, for example, pureenantiomers and/or pure diastereoisomers, such as pure cis/trans isomersor meso-compounds. Accordingly, as isomeric mixtures there may beobtained, for example, enantiomeric mixtures, such as racemates,diastereoisomeric mixtures or mixtures of racemates.

Resulting diastereoisomeric mixtures and mixtures of racemates can beseparated into the pure diastereoisomers or racemates in known manner onthe basis of the physico-chemical differences between the constituents,for example by fractional crystallisation.

Resulting enantiomeric mixtures, such as racemates, can be separatedinto the enantiomers by known methods, for example by recrystallisationfrom an optically active solvent, by chromatography on chiraladsorbents, with the aid of suitable microorganisms, by cleaving withspecific, immobilised enzymes, by means of the formation of inclusioncompounds, for example using chiral Crown ethers, in which case only oneenantiomer is complexed, or by conversion into diastereoisomeric salts,for example by reaction of a basic end product racemate with anoptically active acid, such as a carboxylic acid, for example tartaricor malic acid, or a sulfonic acid, for example camphorsulfonic acid, andseparation of the mixture of diastereoisomers obtained in this manner,for example on the basis of their different solubilities, into thediastereoisomers from which the desired enantiomer can be freed by theaction of suitable agents. Advantageously, the more active enantiomer isisolated.

The invention also relates to those forms of the process according towhich a compound obtainable as intermediate at any stage of the processis used as starting material and the remaining steps are carried out, ora starting material is used in the form of a derivative or salt and/orits racemates or enantiomers or, especially, is formed under thereaction conditions.

In the process of the present invention it is preferable to use thosestarting materials which result in the compounds of formula I describedat the beginning as being especially valuable. The invention relatesalso to novel starting materials which were developed specifically forthe preparation of the compounds of formula I, to their use and toprocess for their preparation, the variables R₁, R₂, R₃, R₄, R₅, X, Z,m, n, p and alk and the substituents of the ring A and the dotted linehaving the meanings indicated for the groups of compounds of formulae I,IA and IB that are preferred in each case.

In this connection, special mention should be made of compounds offormula ##STR29## and their salts. These likewise have nootropicproperties with a degree of action comparable to that of thecorresponding compounds of formulae I and I' and can likewise be used asnootropic active ingredients in medicaments.

Accordingly, the invention relates also to pharmaceutical, especiallynootropic, preparations containing as active ingredient a compound ofthe formula IVc in which R₁ represents carboxy, lower alkoxycarbonyl,carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl oroptionally acylated hydroxymethyl, R₃ represents hydrogen or loweralkyl, R₄ is lower alkyl, R₅ is lower alkyl, p is 0, m is 1, alkrepresents lower alkylene or lower alkylidene, the ring A isunsubstituted or is mono- or poly-substituted by hydroxy, lower alkoxy,lower alkanoyloxy, halogen, lower alkyl and/or by trifluoromethyl, andeither each of X and Z represents an oxygen atom and n represents 1, orX represents a methylene group, Z represents an oxygen atom and nrepresents 1, or X represents an oxygen atom, Z represents a methylenegroup and n represents 1, or X represents a direct bond, Z represents anoxygen atom and n represents 2, or a pharmaceutically acceptable saltthereof, to the use of the mentioned compounds of the formula IVc ortheir pharmaceutically acceptable salts for the manufacture of nootropicpharmaceutical preparations, to a method for the treatment of thesymptoms of cerebral insufficiency, characterised in that one of thementioned compounds of the formula IVc, or a pharmaceutically acceptablesalt thereof, is administered, and to compounds of the formula IVc inwhich R₁ represents carboxy, lower alkoxycarbonyl, carbamoyl, N-loweralkylcarbamoyl, N,N-di-lower alkylcarbamoyl or optionally acylatedhydroxymethyl, R₃ represents hydrogen or lower alkyl, R₄ is lower alkyl,R₅ is lower alkyl, p is 0, m is 1, alk represents lower alkylene orlower alkylidene, the ring A is unsubstituted or is mono- orpoly-substituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen,lower alkyl and/or by trifluoromethyl, and either each of X and Zrepresents an oxygen atom and n represents 1, or X represents amethylene group, Z represents an oxygen atom and n represents 1, or Xrepresents an oxygen atom, Z represents a methylene group and nrepresents 1, or X represents a direct bond, Z represents an oxygen atomand n represents 2, with the proviso that in compounds of the formulaIVc in which the ring A is unsubstituted, each of X and Z representsoxygen, n represents 1 and R₃ represents hydrogen, alk is other thanmethylene if R₁ represents carbamoyl or N-methyl-, N-ethyl-,N,N-dimethyl- or N,N-diethylcarbamoyl, and to their salts, and to aprocess for the manufacture of the latter, novel compounds of theformula IVc and their salts, and to compounds of formula IVc in which R₁is carboxy, lower alkoxycarbonyl, amidated carboxy or free or acylatedhydroxymethyl, R₃ is hydrogen or lower alkyl, R₄ is lower alkyl, R₅ islower alkyl, alk is lower alkylene or lower alkylidene, the ring A isunsubstituted or is mono- or poly-substituted by hydroxy, lower alkoxy,lower alkanoyloxy, cyano, halogen, lower alkyl and/or bytrifluoromethyl, m is 0 or 1, p is 1, Z is an oxygen atom, and in whicheither X is an oxygen atom or a methylene group and n is 0, or X is adirect bond and n is 1, and salts thereof, to the use of the saidcompounds of formula IVc, to a process for the preparation thereof, andto pharmaceutical preparations containing a compound of formula IVc or apharmaceutically acceptable salt thereof.

Accordingly, the invention relates also especially to the groups ofcompounds of the formula IVc which are made up by the compounds of theformulae ##STR30## that is to say, the invention relates also topharmaceutical, especially nootropic, preparations containing as activeingredient a compound of the formula IVcA in which R₁ representscarboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl,N,N-di-lower alkylcarbamoyl or optionally acylated hydroxymethyl, R₃represents hydrogen or lower alkyl, alk represents lower alkylene orlower alkylidene, the ring A is unsubstituted or is mono- orpoly-substituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen,lower alkyl and/or by trifluoromethyl, and either each of X and Yrepresents an oxygen atoms and n represents 1, or X represents amethylene group, Y represents an oxygen atom and n represents 1, or Xrepresents an oxygen atom, Y represents a methylene group and nrepresents 1, or X represents a direct bond, Y represents an oxygen atomand n represents 2, or a pharmaceutically acceptable salt thereof, tothe use of the mentioned compounds of the formula IVcA or theirpharmaceutically acceptable salts for the manufacture of nootropicpharmaceutical preparations, to a method for the treatment of thesymptoms of cerebral insufficiency, characterised in that one of thementioned compounds of the formula IVcA, or a pharmaceuticallyacceptable salt thereof, is administered, and to compounds of theformula IVca in which R₁ represents carboxy, lower alkoxycarbonyl,carbamoyl, N-lower alkylcarbamoyl, N-N-di-lower alkylcarbamoyl oroptionally acylated hydroxymethyl, R₃ represents hydrogen or loweralkyl, alk represents lower alkylene or lower alkylidene, the ring A isunsubstituted or is mono- or poly-substituted by hydroxy, lower alkoxy,lower alkanoyloxy, halogen, lower alkyl and/or by trifluoromethyl, andeither each of X and Y represents an oxygen atom and n represents 1, orX represents a methylene group, Y represents an oxygen atom and nrepresents 1, or X represents an oxygen atom, Y represents a methylenegroup and n represents 1, or X represents a direct bond, Y represents anoxygen atom and n represents 2, with the proviso that in compounds ofthe formula IVcA in which the ring A is unsubstituted, each of X and Yrepresents oxygen, n represents 1 and R₃ represents hydrogen, alk isother than methylene if R₁ represents carbamoyl or N-methyl-, N-ethyl-,N,N-dimethyl- or N,N-diethylcarbamoyl, and to their salts, and to aprocess for the manufacture of the latter, novel compounds of theformula IVcA and their salts, and to compounds of the formula IVcB inwhich R₁ is carboxy, lower alkoxycarbonyl, amidated carboxy or free oracylated hydroxymethyl, R₃ is hydrogen or lower alkyl, R₄ is loweralkyl, R₅ is lower alkyl, alk is lower alkylene or lower alkylidene, thering A is unsubstituted or is mono- or poly-substituted by hydroxy,lower alkoxy, lower alkanoyloxy, cyano, halogen, lower alkyl and/or bytrifluoromethyl, m is 0 or 1, and in which either X is an oxygen atom ora methylene group and n is 0, or X is a direct bond and n is 1, andsalts thereof, to the use of the said compounds of formula IVcB, to aprocess for the preparation thereof, and to pharmaceutical preparationscontaining a compound of formula IVcB or a pharmaceutically acceptablesalt thereof.

Accordingly, the invention relates, for example, also to pharmaceutical,especially nootropic, preparations containing as active ingredient acompound of the formula IVcA in which R₁ represents carboxy, loweralkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl or N,N-di-loweralkylcarbamoyl, R₃ represents hydrogen or lower alkyl, alk representslower alkylene or lower alkylidene, the ring A is unsubstituted or ismono- or poly-substituted by hydroxy, lower alkoxy, lower alkanoyloxy,halogen, lower alkyl and/or by trifluoromethyl, X represents an oxygenatom or a methylene group, Y represents an oxygen atom and n represents1, or a pharmaceutically acceptable salt thereof, to the use of thementioned compounds of the formula IVcA or their pharmaceuticallyacceptable salts for the manufacture of nootropic pharmaceuticalpreparations, to a method for the treatment of the symptoms of cerebralinsufficiency, characterised in that one of the mentioned compounds ofthe formula IVcA or a pharmaceutically acceptable salt thereof, isadministered, and to compounds of the formula IVcA in which R₁represents carboxy, lower alkoxycarbonyl, carbamoyl, N-loweralkylcarbamoyl or N,N-di-lower alkylcarbamoyl, R₃ represents hydrogen orlower alkyl, alk represents lower alkylene or lower alkylidene, the ringA is unsubstituted or is mono- or poly-substituted by hydroxy, loweralkoxy, lower alkanoyloxy, halogen, lower alkyl and/or bytrifluoromethyl, X represents an oxygen atom or a methylene group, Yrepresents an oxygen atom and n represents 1, with the proviso that incompounds of the formula IVcA in which the ring A is unsubstituted, eachof X and Y represents oxygen, n represents 1 and R₃ represents hydrogen,alk is other than methylene if R₁ represents carbamoyl or N-methyl-,N-ethyl-, N,N-di-methyl-, or N,N-diethyl-carbamoyl, and to their salts,and to a process for the manufacture of the latter, novel compounds ofthe formula IVcA and their salts.

The variables in the formula IVc have, for example, the preferredmeanings given under formula I.

The invention relates in this respect especially to pharmaceutical,especially nootropic, preparations and to the manufacture thereof and tomethods of treatment, characterised in that there is selected a compoundof the formula IVcA in which R₁ represents carboxy, loweralkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-loweralkylcarbamoyl, hydroxymethyl, lower alkanoyloxymethyl, loweralkanesulphonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl, R₃represents hydrogen or lower alkyl, alk represents lower alkylene thatlinks the ring system with the NH group shown in formula IVcA by up toand including 3 carbon atoms, or alk represents lower alkylidene, thering A is unsubstituted or is mono-, di-or poly-substituted by hydroxy,lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or bytrifluoromethyl, and either each of X and Y represents an oxygen atomand n represents 1, or X represents a methylene group, Y represents anoxygen atom and n represents 1, or X represents an oxygen atom, Yrepresents a methylene group and n represents 1, or X represents adirect bond, Y represents an oxygen atom and n represents 2, or one ofthe pharmaceutically acceptable salts thereof, and to compounds of theformula IVcA in which R₁ represents carboxy, lower alkoxycarbonyl,carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl,hydroxymethyl, lower alkanoyloxymethyl, lower alkanesulphonyloxymethyl,benzoyloxymethyl or pyridoyloxymethyl, R₃ represents hydrogen or loweralkyl, alk represents lower alkylene that links the ring system with theNH group shown in formula IVcA by up to and including 3 carbon atoms, oralk represents lower alkylidene, the ring A is unsubstituted or ismono-, di- or poly-substituted by hydroxy, lower alkoxy, loweralkanoyloxy, halogen, lower alkyl and/or by trifluoromethyl, and eithereach of X and Y represents an oxygen atom and n represents 1, or Xrepresents a methylene group, Y represents an oxygen atom and nrepresents 1, or X represents an oxygen atom, Y represents a methylenegroup and n represents 1, or X represents a direct bond, Y represents anoxygen atom and n represents 2, with the proviso that in compounds ofthe formula IVcA in which the ring A is unsubstituted, each of X and Yrepresents oxygen, n represents 1 and R₃ represents hydrogen, alk isother than methylene if R₁ represents carbamoyl or N-methyl-, N-ethyl-,N,N-dimethyl-or N,N-diethyl-carbamoyl, and to their salts, and to aprocess for the manufacture of the latter, novel compounds of theformula IVcA and their salts, for example to pharmaceutical, especiallynootropic, preparations and to the manufacture thereof and to methods oftreatment, characterised in that there is selected a compound of theformula IVcA in which R₁ represents carboxy, lower alkoxycarbonyl,carbamoyl, N-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl, R₃represents hydrogen or lower alkyl, alk represents lower alkylene thatlinks the ring system with the NH group shown in formula IVcA by up toand including 3 carbon atoms, or alk represents lower alkylidene, thering A is unsubstituted or is mono-, di- or poly-substituted by hydroxy,lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or bytrifluoromethyl, X represents an oxygen atom or a methylene group, Yrepresents an oxygen atom and n represents 1, or one of thepharmaceutically acceptable salts thereof, and to compounds of theformula IVcA in which R₁ represents carboxy, lower alkoxycarbonyl,carbamoyl, N-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl, R₃represents hydrogen or lower alkyl, alk represents lower alkylene thatlinks the ring system with the NH group shown in formula IVcA by up toand including 3 carbon atoms, or alk represents lower alkylidene, thering A is unsubstituted or is mono-, di- or poly-substituted by hydroxy,lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or bytrifluoromethyl, X represents an oxygen atom or a methylene group, Yrepresents an oxygen atom and n represents 1, with the proviso that incompounds of the formula IVcA in which the ring A is unsubstituted, eachof X and Y represents oxygen, n represents 1 and R₃ represents hydrogen,alk is other than methylene if R₁ represents carbamoyl or N-methyl-,N-ethyl-, N,N-dimethyl-or N,N-diethylcarbamoyl, and to their salts, andto a process for the manufacture of the latter, novel compounds of theformula IVcA and their salts.

In this respect the invention relates more especially to pharmaceutical,especially nootropic, preparations and to the manufacture thereof and tomethods of treatment, characterised in that there is selected a compoundof the formula IVcA in which R₁ represents carboxy, hydroxymethyl, C₂-C₅ -alkanoyloxymethyl, such as acetoxymethyl, C₁ -C₄ -alkoxycarbonyl,such as methoxycarbonyl, or carbamoyl, R₃ represents hydrogen or C₁ -C₄-alkyl, such as methyl, alk represents C₁ -C₄ -alkylene that links thering system with the NH group shown in formula IVcA by up to andincluding 3 carbon atoms, such as methylene or ethylene, the ring A isunsubstituted or is substituted, especially in the 7-position, by C₁ -C₄-alkoxy, such as methoxy, and either each of X and Y represents anoxygen atom and n represents 1, or X represents a methylene group, Yrepresents an oxygen atom and n represents 1, or X represents an oxygenatom, Y represents a methylene group and n represents 1, or X representsa direct bond, Y represents an oxygen atom and n represents 2, on one ofthe pharmaceutically acceptable salts thereof, and to compounds of theformula IVcA in which R₁ represents carboxy, hydroxymethyl, C₂ -C₅-alkanoyloxymethyl, such as acetoxymethyl, C₁ -C₄ -alkoxycarbonyl, suchas methoxycarbonyl, or carbamoyl, R₃ represents hydrogen or C₁ -C₄-alkyl, such as methyl, alk represents C₁ -C₄ -alkylene that links thering system with the NH group shown in formula IVcA by up to andincluding 3 carbon atoms, such as methylene or ethylene, the ring A isunsubstituted or is substituted, especially in the 7-position, by C₁ -C₄-alkoxy, such as methoxy, and either each of X and Y represents anoxygen atom and n represents 1, or X represents a methylene group, Yrepresents an oxygen atom and n represents 1, or X represents an oxygenatom, Y represents a methylene group and n represents 1, or X representsa direct bond, Y represents an oxygen atom and n represents 2, with theproviso that in compounds of the formula IVcA in which the ring A isunsubstituted, each of X and Y represents oxygen, n represents 1 and R₃represents hydrogen, alk is other than methylene if R₁ representscarbamoyl, and to their salts, and to a process for the manufacture ofthe latter, novel compounds of the formula IVcA and their salts, forexample pharmaceutical, especially to nootropic, preparations and to themanufacture thereof, and to methods of treatment, characterised in thatthere is selected a compound of the formula IVcA in which R₁ representsC₁ -C₄ -alkoxycarbonyl, such as methoxycarbonyl, R₃ represents hydrogenor C₁ -C₄ -alkyl, such as methyl, alk represents C₁ -C₄ -alkylene thatlinks the ring system with the NH group shown in formula IVcA by up toand including 3 carbon atoms, such as methylene or ethylene, the ring Ais unsubstituted, X represents an oxygen atom or a methylene group, Yrepresents an oxygen atom and n represents 1, or one of thepharmaceutically acceptable salts thereof, and to compounds of theformula IVcA in which R₁ represents C₁ -C₄ -alkoxycarbonyl, such asmethoxycarbonyl, R₃ represents hydrogen or C₁ -C₄ -alkyl, such asmethyl, alk represents C₁ -C₄ -alkylene that links the ring system withthe NH group shown in formula IVcA by up to and including 3 carbonatoms, such as methylene or ethylene, the ring A is unsubstituted, Xrepresents an oxygen atom or a methylene group, Y represents an oxygenatom and n represents 1, and to their salts, and to a process for themanufacture of the latter, novel compounds of the formula IVcA and theirsalts.

In this respect the invention relates most especially to pharmaceutical,especially nootropic, preparations and to the manufacture thereof, andto methods of treatment, characterised in that there is selected acompound of the formula IVcA in which R₁ represents C₁ -C₄-alkoxycarbonyl, such as methoxycarbonyl, R₃ represents hydrogen, alkrepresents methylene or ethylene, the ring A is unsubstituted, Xrepresents an oxygen atom or a methylene group, Y represents an oxygenatom and n represents 1, or one of the pharmaceutically acceptable saltsthereof, and to compounds of the formula IVcA in which R₁ represents C₁-C₄ -alkoxycarbonyl, such as methoxycarbonyl, R₃ represents hydrogen,alk represents methylene or ethylene, the ring A is unsubstituted, Xrepresents an oxygen atom or a methylene group, Y represents an oxygenatom and n represents 1, and to their salts, and to a process for themanufacture of the latter, novel compounds of the formula IVcA and theirsalts.

In this respect the invention relates especially to compounds of formulaIVcB in which R₁ is carboxy, lower alkoxycarbonyl, carbamoyl, N-loweralkylcarbamoyl, N,N-di-lower alkylcarbamoyl, N,N-loweralkylenecarbamoyl, N,N-(aza)-, N,N-(oxa)- or N,N-(thia)-loweralkylenecarbamoyl, hydroxymethyl, lower alkanoyloxymethyl, loweralkanesulfonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl, R₃ ishydrogen or lower alkyl, R₄ is lower alkyl, R₅ is lower alkyl, alk islower alkylene that links the ring system with the NH group shown informula IVcB by up to and including 3 carbon atoms or is loweralkylidene, the ring A is unsubstituted or is mono-, di- orpoly-substituted by hydroxy, lower alkoxy, lower alkanoyloxy, cyano,halogen, lower alkyl and/or by trifluoromethyl, m is 0 or 1, and inwhich either X is an oxygen atom or a methylene group and n is 0, or Xis a direct bond and n is 1, and salts thereof.

In this respect the invention relates more especially to compounds offormula IVcB in which R₁ is C₁ -C₄ alkoxycarbonyl, such asmethoxycarbonyl or ethoxycarbonyl, carbamoyl, N,N-loweralkylenecarbamoyl, such as piperidinocarbonyl, N,N-(aza)-loweralkylenecarbamoyl, such as piperazinocarbonyl, N,N-(oxa)-loweralkylenecarbamoyl, such as morpholinocarbonyl, or N,N-(thia)-loweralkylenecarbamoyl, such as thiomorpholinocarbonyl, R₃ is hydrogen, R₄ isC₁ -C₄ alkyl, such as methyl, R₅ is C₁ -C₄ alkyl, such as methyl, alk isC₁ -C₄ alkylene that links the ring system with the NH group shown informula IVcB by up to and including 3 carbon atoms, such as methylene orethylene, the ring A is unsubstituted or is substituted, especially inthe 6-position, by C₁ -C₄ alkoxy, such as methoxy, C₁ -C₄ alkyl, such asmethyl, halogen having an atomic number of up to and including 35, suchas fluorine or chlorine, cyano or by trifluoromethyl, m is 0 or 1, X isan oxygen atom or a methylene group and n is 0, and salts thereof.

In this respect the invention relates especially to compounds of formulaIVcB in which R₁ is C₁ -C₄ alkoxycarbonyl, such as methoxycarbonyl orethoxycarbonyl, or carbamoyl, R₃ is hydrogen, R₄ is C₁ -C₄ alkyl, suchas methyl, R₅ is C₁ -C₄ alkyl, such as methyl, alk is C₁ -C₄ alkylenethat links the ring system with the NH group shown in formula IVcB by upto and including 3 carbon atoms, such as methylene or ethylene, the ringA is unsubstituted or is monosubstituted, especially in the 6-position,by halogen having an atomic number of up to and including 35, such asfluorine or chlorine, m is 1, X is a methylene group and n is 0, andsalts thereof.

In this respect the invention relates more especially to compounds offormula IVcB in which R₁ is C₁ -C₄ alkoxycarbonyl, such asmethoxycarbonyl, or carbamoyl, R₃ is hydrogen, R₄ is C₁ -C₄ alkyl, suchas methyl, R₅ is C₁ -C₄ alkyl, such as methyl, alk is ethylene, the ringA is unsubstituted, m is 1, X is a methylene group and n is 0, and saltsthereof.

In this respect the invention relates specifically to pharmaceutical,especially nootropic, preparations and to the manufacture thereof and tomethods of treatment, characterised in that there is selected one of thenovel compounds of the formula IVc mentioned in the Examples, or one ofthe pharmaceutically acceptable salts thereof, and to the novelcompounds of the formula IVc mentioned in the Examples and to theirsalts, and to processes for the manufacture of the latter, novelcompounds of the formula IVc and their salts.

The present invention relates also to a process for the preparation ofcompounds of formula IVc or their salts, in which process, for example,

h) compounds of the formulae ##STR31## in which one of the radicals Z₁and Z₂ is reactive esterified hydroxy, the other is amino and Z₃ ishydrogen, or Z₁ is amino and Z₂ and Z₃ together are an additional bond,or optionally salts of these compounds, are reacted with one another, or

i) in a compound of formula ##STR32## in which X₆ is a radical that canbe converted into R₁, or in a salt thereof, X₆ is converted into R₁,and, in the case of each of process variants h) and i), a protectinggroup which may be present is removed, and, if desired, a compound offormula IVc obtainable in accordance with the process or by other meansis converted into a different compound of formula IVc, an isomericmixture obtainable in accordance with the process is separated into thecomponents, an enantiomeric or diastereoisomeric mixture obtainable inaccordance with the process is separated into the enantiomers ordiastereoisomers, respectively, and/or a free compound of formula IVcobtainable in accordance with the process is converted into a salt or asalt obtainable in accordance with the process is converted into thefree compound of formula IVc or into a different salt.

Variant h)

Reactive esterified hydroxy Z₁ and Z₂ is especially hydroxy esterifiedby a strong inorganic acid or organic sulfonic acid, for examplehalogen, such as chlorine, bromine or iodine, sulfonyloxy, such ashydroxysulfonyloxy, halosulfonyloxy, for example fluorosulfonyloxy,lower alkanesulfonyloxy that is unsubstituted or substituted, forexample by halogen, for example methane- ortrifluoromethane-sulfonyloxy, cycloalkanesulfonyloxy, for examplecyclohexanesulfonyloxy, or benzenesulfonyloxy that is unsubstituted orsubstituted, for example, by lower alkyl or by halogen, for examplep-bromophenyl- or p-toluene-sulfonyloxy.

The reaction is in this case carried out especially in the presence of acondensation agent, such as a suitable base. Suitable bases are, forexample, alkali metal hydroxides, hydrides, amides, alkanolates,carbonates, triphenylmethylides, di-lower alkylamides, amino-loweralkylamides or lower alkylsilylamides, or naphthaleneamines, loweralkylamines, basic heterocycles, ammonium hydroxides and carbocyclicamines. There may be mentioned by way of example: sodium hydroxide,hydride, amide or ethanolate, potassium tert.-butanolate or carbonate,lithium triphenylmethylide, lithium diisopropylamide, potassium3-(aminopropyl)-amide or bis-(trimethylsilyl)-amide, ordimethylaminonaphthalene, di- or triethylamine, pyridine,benzyltrimethylammonium hydroxide, 1,5-diazabicyclo[4.3.0]non-5-ene(DBN) and 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU). The reaction ofamines VIIIa (Z₁ =amino) with acrylic acid compounds VIIIb (Z₂ +Z₃=bond) is effected, for example, with heating, for example atapproximately 60°-120° C.

The starting materials of formulae VIIIa and VIIIb are known or can beprepared analogously to known processes.

Variant i)

A radical X₆ that can be converted into R₁ is, for example, functionallymodified carboxy other than R₁, such as cyano, anhydridised carboxy,unsubstituted or substituted amidino, free, esterified or anhydridisedcarboximidoyl, esterified or amidated carboxy other than esterified oramidated carboxy R₁, tri-lower alkoxymethyl or trihalomethyl.

Anhydridised carboxy is, for example, carboxy anhydridised with amineral acid, such as a hydrohalic acid, or with a carboxylic acid, suchas an unsubstituted or substituted lower alkanoic or benzoic acid, orwith a carbonic acid halide lower alkyl semiester. Examples that may bementioned are halocarbonyl, such as chlorocarbonyl, loweralkanoyloxycarbonyl, such as acetoxycarbonyl, or loweralkoxycarbonyloxycarbonyl, such as ethoxycarbonyloxycarbonyl.

Substituted amidino is, for example, amidino substituted by an aliphaticradical, for example lower alkyl, such as lower alkylamidino, forexample ethylamidino.

Esterified or anhydridised carboximidoyl is to be understood as being,for example, alkoxy- or halo-carboximidoyl, for example lower alkoxy-,such as ethoxy-, or chloro-carboximidoyl.

Tri-lower alkoxy- or tri-halo-methyl is, for example, trimethoxymethylor trichloromethyl, respectively.

X₆ can be converted into R₁, for example, by solvolysis. Solvolysisagents are, for example, water, lower alkanols corresponding to thedesired esterified carboxy R₁, ammonia, or amines corresponding to thedesired amidated carboxy group R₁. The treatment with a correspondingsolvolysis agent is optionally carried out in the presence of an acid orbase. Suitable acids are, for example, inorganic or organic protonicacids, such as mineral acids, for example sulfuric acid or a hydrohalicacid, for example hydrochloric acid, sulfonic acids, for example loweralkanesulfonic acid or unsubstituted or substituted benzenesulfonicacid, for example methane- or p-toluene-sulfonic acid, or carboxylicacids, for example lower alkanecarboxylic acids, for example aceticacid, whilst bases that may be used are, for example, those mentionedunder Variant h), especially sodium or potassium hydroxide.

In the solvolysis, the cyano group, anhydridised carboxy, unsubstitutedor substituted amidino, free, esterified or anhydridised carboximidoyl,esterified or amidated carboxy other than esterified or amidated carboxyR₁, tri-lower alkoxymethyl or trihalomethyl is hydrolysed to carboxy.Lower alkanoyloxy radicals which may be present at the ring A may alsobe hydrolysed to hydroxy in the course of the hydrolysis.

Cyano, anhydridised carboxy, and esterified or amidated carboxy otherthan esterified or amidated carboxy R₁ are alcoholysed, for example witha suitable lower alkanol, to esterified carboxy R₁, and cyano andanhydridised carboxy are ammonolysed or aminolysed, for example withammonia or with an amine corresponding to the amidated carboxy R₁.

The starting material of formula IX can be obtained, for example, byreaction of compounds of the formulae ##STR33## in which one of theradicals Z₁ and Z₂ is reactive esterified hydroxy, the other is aminoand Z₃ is hydrogen, or Z₁ is amino and Z₂ and Z₃ together are anadditional bond, or optionally salts of these compounds, the operationbeing carried out in a manner analogous to that described under ProcessVariant h), for example in the presence of a basic agent. Reactiveesterified hydroxy Z₁ and Z₂ has, for example, one of the meanings givenunder Process Variant h).

In the starting materials of formula VIIIb, a hydroxymethyl group R₁ maybe in etherified or intermediately protected form. Etherifiedhydroxymethyl is, for example, lower alkoxymethyl, such as methoxy- orethoxymethyl, or unsubstituted or substituted phenyl-lower alkoxymethyl,for example phenyl-C₁ -C₄ alkoxymethyl substituted in the phenyl moiety,such as benzyloxy-, p-chlorobenzyloxy-, 1-phenylethoxy- or1-(p-bromophenyl)-n-butoxy-methyl. Protected hydroxymethyl is, forexample, silyloxymethyl, such as tri-lower alkylsilyloxy-, for exampletrimethylsilyloxy-methyl, but may also be triphenyl-lower alkoxy-, forexample trityloxy-methyl.

The freeing of intermediately protected radicals R₁, that is to say theremoval of the intermediate protecting groups, is effected in customarymanner, for example by solvolysis, such as mild hydrolysis, for exampletreatment with water under neutral or weakly acidic conditions, forexample by the action of dilute aqueous mineral or carboxylic acids, forexample dilute hydrochloric or acetic acid.

Subsequent operations which may, if desired, be carried out on compoundsof formula IVc obtained in accordance with the process or by other meansare especially conversions of R₁ and of substituents of the ring A,separations of enantiomers and diastereoisomers and conversions into oneanother of salts and free compounds of formula IVc, analogous to thoseindicated for the compounds of formula I and are carried out inanalogous manner.

The invention relates also to the use of compounds of formula I and IVcand, where appropriate, their tautomers and/or pharmaceuticallyacceptable salts of such compounds having salt-forming properties,especially as pharmacological, more especially nootropically active,active ingredients. They can be used, preferably in the form ofpharmaceutically acceptable preparations, in a method for theprophylactic and/or therapeutic treatment of the animal or human body,especially as nootropics, for example for the treatment of the symptomsof cerebral insufficiency, especially memory disorders.

The invention relates also to pharmaceutical preparations that containas active ingredient a compound of formula I or IVc, or, whereappropriate, a tautomer and/or pharmaceutically acceptable salt thereof,and to processes for their preparation.

The pharmaceutical preparations according to the invention, whichcontain a compound of formula I or IVc or, where appropriate, a tautomerand/or pharmaceutically acceptable salt thereof, are for enteral, suchas oral, and also rectal, and parenteral administration to warm-bloodedanimals, the preparations containing the pharmacological activeingredient alone or together with customary pharmaceutical adjuncts.

The novel pharmaceutical preparations contain, for example, fromapproximately 10% to approximately 80%, preferably from approximately20% to approximately 60%, active ingredient. Pharmaceutical preparationsaccording to the invention for enteral or parenteral administration are,for example, those in dosage unit forms, such as dragees, tablets,capsules or suppositories, and also ampoules. They are manufactured in amanner known per se, for example by means of conventional mixing,granulating, confectioning, dissolving or lyophilising processes. Thus,pharmaceutical preparations for oral use can be obtained by combiningthe active ingredient with solid carriers, optionally granulating theresulting mixture, and processing the mixture or granulate, if desiredor necessary after the addition of suitable adjuncts, to form tablets ordragee cores.

Suitable carriers are especially fillers, such as sugars, for examplelactose, saccharose, mannitol or sorbitol, cellulose preparations and/orcalcium phosphate, for example tricalcium phosphate or calcium hydrogenphosphate, also binders such as starch pastes using, for example, corn,wheat, rice or potato starch, gelatine, tragacanth, methylcelluloseand/or polyvinylpyrrolidone, if desired, disintegrators, such as theabove-mentioned starches, also carboxymethyl starch, cross-linkedpolyvinylpyrrolidone, agar, alginic acid or a salt thereof, such assodium alginate. Adjuncts are especially flow-regulating agents andlubricants, for example silica, talc, stearic acid or salts thereof,such as magnesium or calcium stearate, and/or polyethylene glycol.Dragee cores are provided with suitable coatings which may be resistantto gastric juices, there being used, inter alia, concentrated sugarsolutions which may contain gum arabic, talc, polyvinylpyrrolidone,polyethylene glycol and/or titanium dioxide, or lacquer solutions insuitable organic solvents or solvent mixtures, or, for the production ofcoatings resistant to gastric juices, solutions of suitable cellulosepreparations, such as acetylcellulose phthalate orhydroxypropylmethylcellulose phthalate. Colourings or pigments may beadded to the tablets or dragee coatings, for example for identificationpurposes or to indicate different doses of active ingredient.

Further orally administrable pharmaceutical preparations are dry-filledcapsules consisting of gelatine, and also soft, sealed capsulesconsisting of gelatine and a plasticiser, such as glycerol or sorbitol.The dry-filled capsules may contain the active ingredient in the form ofa granulate, for example in admixture with fillers, such as lactose,binders, such as starches, and/or glidants, such as talc or magnesiumstearate, and optionally stabilisers. In soft capsules, the activeingredient is preferably dissolved or suspended in suitable liquids,such as fatty oils, paraffin oil or liquid polyethylene glycols, towhich stabilisers may likewise be added.

There come into consideration as rectally administrable pharmaceuticalpreparations, for example, suppositories that consist of a combinationof the active ingredient and a suppository base. Suitable suppositorybases are, for example, natural or synthetic triglycerides, paraffinhydrocarbons, polyethylene glycols or higher alkanols. It is alsopossible to use gelatine rectal capsules that contain a combination ofthe active ingredient and a base material. Suitable base materials are,for example, liquid triglycerides, polyethylene glycols or paraffinhydrocarbons.

Suitable for parenteral administration are especially aqueous solutionsof an active ingredient in water-soluble form, for example awater-soluble salt, and also suspensions of the active ingredient, suchas corresponding oily injection suspensions, there being used suitablelipophilic solvents or vehicles, such as fatty oils, for example sesameoil, or synthetic fatty acid esters, for example ethyl oleate ortriglycerides, or aqueous injection suspensions that containviscosity-increasing substances, for example sodiumcarboxymethylcellulose, sorbitol and/or dextran and, optionally, alsostabilisers.

The dosage of the active ingredient can depend upon various factors,such as the method of administration, the species of warm-bloodedanimal, age and/or individual condition. In normal cases, theapproximate daily dose for a warm-blooded animal weighing about 75 kg isestimated to be, in the case of oral administration, from approximately20 mg to approximately 500 mg, especially from approximately 25 mg toapproximately 250 mg, advantageously in several equal partial doses.

The following Examples illustrate the invention described above but arenot intended to limit the scope thereof in any way. Temperatures aregiven in degrees Celsius.

As a result of the close relationship between a compound of formula Iand the corresponding tautomeric compound of formula I', in the Examplesa compound of formula I should be understood as meaning also thetautomeric compound of formula I' where appropriate and expedient. Thesame applies to a compound of formula I' and to salts of compounds offormulae I and I'.

EXAMPLE 1

First 5.55 g (25 mmol) of 1,2,5,6-tetrahydropyridine-3-carboxylic acidmethyl ester hydrobromide (guvacoline hydrobromide) and then 11.31 g(87.5 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of7.96 g (25 mmol) of 3-(p-toluenesulphonyloxymethyl)chroman in 100 ml ofdimethylformamide. The mixture is stirred for 15 hours at 50° and thenconcentrated by evaporation under a high vacuum. Water is added to theresidue and extraction is carried out with diethyl ether. The organicphases are washed with water and extracted with 2N hydrochloric acid.The hydrochloric acid extracts are combined, rendered alkaline, whilecold, with sodium hydroxide solution (30% strength) and extracted withdichloromethane. The combined organic phases are dried over sodiumsulphate and concentrated by evaporation in vacuo. 5.92 g (83%) of1-(chroman-3-ylmethyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acidmethyl ester are obtained in the form of a pale yellow oil. The1-(chroman-3-ylmethyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acidmethyl ester hydrochloride produced therefrom using hydrochloric acid indiethyl ether melts at 158°-159° after crystallisation frommethanol/diethyl ether.

3-(p-toluenesulphonyloxymethyl)chroman can be manufactured, for example,as follows:

At room temperature and while stirring, a solution of 50.0 g (260 mmol)of 3-methoxycarbonylchroman (U.S. Pat. No. 4,178,380) in 200 ml ofabsolute tetrahydrofuran is added dropwise within a period of 40 minutesto a suspension of 9.86 g (260 mmol) of lithium aluminium hydride in 300ml of absolute diethyl ether. After stirring for 16 hours at roomtemperature, the reaction mixture is decomposed with 9.9 ml of water,9.9 ml of sodium hydroxide solution (15% strength) and 30 ml of water.The precipitate formed is filtered off with suction and the filtrate isconcentrated to dryness by evaporation in vacuo. The oily residue isdissolved in diethyl ether and the solution is washed with water, driedover sodium sulphate and concentrated to dryness by evaporation. 36.71 g(86%) of oily 3-hydroxymethylchroman, which crystallises from diethylether/pentane and melts at 60°-61°, are obtained.

46.14 g (242 mmol) of p-toluenesulphonyl chloride are added whilestirring at room temperature to a solution of 36.12 g (220 mmol) of3-hydroxymethylchroman in 100 ml of absolute pyridine, the slightlyexothermic reaction being maintained at room temperature by means of anice bath. The reaction mixture is stirred for a further 3 hours at roomtemperature and then poured onto ice-water. The crystals formed arefiltered off with suction, washed with water and dried in vacuo. 65.84 g(94%) of 3-(p-toluenesulphonyloxymethyl)chroman having a melting pointof 86°-87° are obtained.

EXAMPLE 2

At room temperature and while stirring, 0.75 g (15.6 mmol) of sodiumhydride dispersion in mineral oil (50%) is added within a period of 30minutes to a solution of 4.36 g (13 mmol) ofN,N-bis-(2-methoxycarbonylethyl)-N-(chroman-3-ylmethyl)-amine in 50 mlof absolute dimethylformamide. The reaction mixture is stirred for afurther 1 hour at room temperature and then concentrated by evaporationunder a high vacuum. Diethyl ether is added to the resulting residue andextraction is carried out with cold 2N hydrochloric acid. The combinedhydrochloric acid extracts are extracted by shaking with dichloromethaneand the combined dichloromethane extracts are dried over sodium sulphateand concentrated by evaporation. There are obtained 3.8 g (85.8%) ofcrystalline4-hydroxy-1-(chroman-3-ylmethyl)-1,2,5,6-tetrahydropyridine-3-carboxylicacid methyl ester hydrochloride or1-(chroman-3-ylmethyl)-4-oxo-piperidine-3-carboxylic acid methyl esterhydrochloride, respectively, which, after recrystallisation frommethanol/diethyl ether has a decomposition point of 167°-168°.

N,N-bis(2-methoxycarbonylethyl)-N-(chroman-3-ylmethyl)-amine can bemanufactured, for example, in the following manner:

First 1.77 g (13.32 mmol) of aluminium chloride in 50 ml of absolutediethyl ether are added dropwise while stirring at room temperature to asuspension of 3.04 g (80 mmol) of lithium aluminium hydride in 100 ml ofabsolute diethyl ether. Then 6.29 g (40 mmol) of 3-cyanochromene [R. C.Gupta et al., Ind. J. Chem. 21B, 344 (1982)] in 50 ml of absolutetetrahydrofuran are added dropwise within a period of 20 minutes. Thereaction mixture is boiled under reflux for 16 hours. After it hascooled, it is carefully decomposed with 3.1 ml of water, 3.1 ml ofsodium hydroxide solution (15% strength) and 9.3 ml of water. Theprecipitate formed is filtered off with suction, the filtrate isconcentrated by evaporation in vacuo and the oily residue is dissolvedin diethyl ether. The organic phase is washed with water and extractedwith 2N hydrochloric acid. The combined hydrochloric acid extracts arerendered alkaline, while cold, with sodium hydroxide solution (30%strength) and extracted by shaking with dichloromethane. After dryingthe combined organic phases over sodium sulphate and concentrating invacuo, 3.5 g (53.6%) of 3-aminomethylchroman are obtained in the form ofa yellow oil. The 3-aminomethylchroman hydrochloride produced therefromusing hydrochloric acid in diethyl ether is recrystallised frommethanol/diethyl ether and melts at 218°-219°.

3.03 g (35.2 mmol) of acrylic acid methyl ester are added to a solutionof 2.61 g (16 mmol) of 3-aminomethylchroman in 20 ml of methanol. Thereaction solution is stirred for 16 hours at 50° and, after cooling, isconcentrated by evaporation in vacuo. 5.1 g (95%) ofN,N-bis(2-methoxycarbonylethyl)-N-(chroman-3-ylmethyl)-amine areobtained in the form of a reddish oil.

EXAMPLE 3

A solution of 10.48 g (30 mmol) ofN-[2-(chroman-3-yl)ethyl]-N,N-bis(2-methoxycarbonylethyl)-amine in 35 mlof absolute dimethylformamide is added dropwise at room temperature andwhile stirring to a suspension of 2.16 g (40 mmol) of sodium methoxidein 25 ml of dimethylformamide within a period of 15 minutes. Thereaction mixture is stirred for 16 hours at room temperature and thenconcentrated to dryness by evaporation under a high vacuum. Diethylether is added to the residue and extraction is carried out with cold 2Nhydrochloric acid. The combined hydrochloric acid extracts are extractedby shaking with dichloromethane and the dichloromethane phases are driedover sodium sulphate and concentrated by evaporation in vacuo. There areobtained 4.25 g (40%) of1-[2-(chroman-3-yl)ethyl]-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylicacid methyl ester hydrochloride or1-[2-(chroman-3-yl)ethyl]-4-oxopiperidine-3-carboxylic acid methyl esterhydrochloride, respectively, which after recrystallisation frommethanol/diethyl ether, has a decomposition point of 175° -177°.

N-[2-(chroman-3-yl)ethyl]-N,N-bis(2-methoxycarbonylethyl)-amine can bemanufactured, for example, in the following manner:

12.53 g (192.5 mmol) of potassium cyanide are added at room temperatureto a solution of 55.72 g (175 mmol) of3-(p-toluenesulphonyloxymethyl)chroman (for manufacture see Example 1)in 300 ml of dimethyl sulphoxide and the whole is heated to 60° whilestirring. After 3 hours, ice-water is added to the reaction mixture, thewhole is extracted with diethyl ether and washed thoroughly with water.The combined organic phases are dried over sodium sulphate andconcentrated by evaporation in vacuo. 26.75 g (88.3%) of3-cyanomethylchroman are obtained in the form of a pale yellow oil whichcrystallises from diethyl ether/pentane. The crystals melt at 63°.

First 4.44 g (33.3 mmol) of aluminium chloride in 150 ml of absolutediethyl ether are added dropwise while stirring at room temperature to asuspension of 7.59 g (200 mmol) of lithium aluminium hydride in 300 mlof absolute diethyl ether. Then 17.32 g (100 mmol) of3-cyanomethylchroman, dissolved in 200 ml of tetrahydrofuran, are addeddropwise within a period of 15 minutes. The reaction mixture is stirredfor 16 hours at room temperature and then decomposed with 7.6 ml ofwater, 7.6 ml of sodium hydroxide solution (15% strength) and 22.8 ml ofwater. The precipitate formed is filtered off with suction and thefiltrate is concentrated by evaporation in vacuo. The oily residue isdissolved in diethyl ether and washed with water. The organic phase isthen extracted by shaking with 2N hydrochloric acid. The combinedhydrochloric acid extracts are rendered alkaline, while cold, withsodium hydroxide solution (30% strength) and extracted withdichloromethane. The combined organic phases are dried over sodiumsulphate and concentrated by evaporation in vacuo. 15.95 g (90%) of3-(2-aminoethyl)chroman are obtained in the form of a colourless oil.The 3-(2-aminoethyl)chroman hydrochloride produced therefrom usinghydrochloric acid in diethyl ether crystallises from methanol/diethylether and has a melting point of 244°-245°.

6.63 g (77 mmol) of acrylic acid methyl ester are added at roomtemperature to a solution of 6.2 g (35 mmol) of 3-(2-aminoethyl)chromanin 50 ml of methanol and the whole is stirred for 16 hours at roomtemperature. The reaction mixture is then concentrated by evaporation invacuo and yields 12.23 g (100%) ofN-[2-(chroman-3-yl)ethyl]-N,N-bis(2-methoxycarbonylethyl)-amine in theform of a reddish oil.

EXAMPLE 4

In a manner analogous to that described in Example 3, by reacting3-(2-aminoethyl)chroman with 1 equivalent of acrylic acid methyl ester,it is possible to manufacture the correspondingN-[2-(chroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine whosehydrochloride melts at 190°-192°.

EXAMPLE 5

In a manner analogous to that described in Examples 3 and 4, by reacting3-aminomethylchroman with 1 equivalent of acrylic acid methyl ester, itis possible to manufactureN-(2-methoxycarbonylethyl)-N-(chroman-3-ylmethyl)-amine or itshydrochloride.

EXAMPLE 6

First 3.3 g (14.8 mmol) of 1,2,5,6-tetrahydropyridine-3-carboxylic acidmethyl ester hydrobromide (guvacoline hydrobromide) and then 6.1 g (47.3mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 4.5 g(13.5 mmol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman in 70 ml ofabsolute dimethylformamide. The mixture is stirred for 16 hours at 60°and, after cooling, is concentrated by evaporation under a high vacuum.Water is added to the oily residue and extraction is carried out withdiethyl ether. The combined organic phases are extracted with 2Nhydrochloric acid. The combined hydrochloric acid extracts are renderedalkaline, while cold, with sodium hydroxide solution (30% strength) andextracted with dichloromethane. The combined dichloromethane phases aredried over sodium sulphate and concentrated by evaporation in vacuo.3.97 g (97.7%) of1-[2-(chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acidmethyl ester are obtained in the form of a yellow oil. The1-[2-(chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acidmethyl ester hydrochloride produced therefrom using hydrochloric acid indiethyl ether crystallises from methanol/diethyl ether and melts at175°-177°.

3-[2-(p-toluenesulphonyloxy)ethyl]chroman can be manufactured, forexample, as follows:

50 ml of 2N sodium hydroxide solution are added to a solution of 7.8 g(45 mmol) of 3-cyanomethylchroman in 150 ml of ethanol and the whole isboiled under reflux for 16 hours. After cooling, the reaction mixture isconcentrated by evaporation in vacuo. The residue is dissolved in waterand extracted with diethyl ether. The aqueous phase is acidified withhydrochloric acid (36% strength) and extracted by shaking withdichloromethane. The combined dichloromethane extracts are dried oversodium sulphate and concentrated by evaporation in vacuo. 8.3 g (96%) of3-carboxymethylchroman are obtained in the form of colourless crystalswhich melt at 106°-107°.

1.5 ml of sulphuric acid (100% strength) are added to a solution of 7.69g (40 mmol) of 3-carboxymethylchroman in 150 ml of methanol and thewhole is boiled under reflux for 3 hours. After cooling, the reactionmixture is concentrated by evaporation in vacuo. The residue isdissolved in diethyl ether and washed, while cold, with water, sodiumhydrogen carbonate and again with water. The combined organic phases aredried over sodium sulphate and concentrated by evaporation in vacuo.8.08 g (98%) of 3-methoxycarbonylmethylchroman are obtained in the formof a pale yellow oil.

At room temperature and while stirring, a solution of 7.22 g (35 mmol)of 3-methoxycarbonylmethylchroman in 50 ml of absolute tetrahydrofuranis added dropwise within a period of 30 minutes to a suspension of 1.33g (35 mmol) of lithium aluminium hydride in 50 ml of absolute diethylether. Stirring is continued at room temperature for a further 16 hoursand then the whole is carefully decomposed with 1.33 ml of water, 1.33ml of sodium hydroxide solution (15% strength) and 4.0 ml of water. Theprecipitate formed is filtered off with suction and the filtrate isconcentrated by evaporation in vacuo. The oily residue is dissolved indiethyl ether. The solution is washed with water, dried over sodiumsulphate and concentrated by evaporation in vacuo. 6.23 g (100%) of3-(2-hydroxyethyl)chroman are obtained in the form of a yellow oil.

6.29 g (33 mmol) of p-toluenesulphonyl chloride are added while stirringat room temperature to a solution of 5.35 g (30 mmol) of3-(2-hydroxyethyl)chroman in 30 ml of absolute pyridine, the slightlyexothermic reaction being maintained at room temperature by means of anice bath. After stirring for a further three hours at room temperature,the reaction mixture is poured onto ice-water. The crystals formed arefiltered off with suction, washed with water and dried in vacuo. 5.9 g(59.2%) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman, which melts at91°-93°, are obtained.

EXAMPLE 7

First 11.1 g (50 mmol) of 1,2,5,6-tetrahydropyridine-3-carboxylic acidmethyl ester hydrobromide (guvacoline hydrobromide) and then 22.6 g (175mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 11.45 g(50 mmol) of 2-bromomethylbenzo-1,4-dioxan (U.S. Pat. No. 2,366,102) in100 ml of absolute dimethylformamide. The mixture is stirred for 16hours at 50° and then concentrated by evaporation under a high vacuum.Water is added to the residue and extraction is carried out with diethylether. The organic phases are washed with water and extracted by shakingwith 2N hydrochloric acid. The combined hydrochloric acid extracts arerendered alkaline, while cold, with sodium hydroxide solution (30%strength) and extracted with dichloromethane. The combineddichloromethane phases are dried over sodium sulphate and concentratedby evaporation in vacuo. 10.75 g (74.4%) of1-(benzo-1,4-dioxan-2-ylmethyl)-1,2,5,6-tetrahydropyridine-3-carboxylicacid methyl ester are obtained in the form of a yellow oil. The1-(benzo-1,4-dioxan-2-ylmethyl)-1,2,5,6-tetrahydropyridine- 3-carboxylicacid methyl ester hydrochloride produced therefrom using hydrochloricacid in diethyl ether crystallises from methanol/diethyl ether anddecomposes at 215°-217°.

EXAMPLE 8

0.5 g of palladium-on-carbon (5%) is added to a solution of 4.88 g (15mmol) of1-(benzo-1,4-dioxan-2-ylmethyl)-1,2,5,6-tetrahydropyridine-3-carboxylicacid methyl ester hydrochloride in 100 ml of methanol and the whole ishydrogenated for 6 hours at room temperature and at normal pressure. Thecatalyst is then filtered off with suction and the filtrate isconcentrated by evaporation in vacuo. The oily residue is dissolved inhot acetone and diethyl ether is added until the solution becomesturbid. 4.08 g (83%) of1-(benzo-1,4-dioxan-2-ylmethyl)-piperidine-3-carboxylic acid methylester hydrochloride having a melting point of 186°-188° crystallise out.

EXAMPLE 9

At room temperature and while stirring, a solution of 10.12 g (30 mmol)of N,N-bis(2-methoxycarbonylethyl)-N-(benzo-1,4-dioxan-2-ylmethyl)-aminein 25 ml of absolute dimethylformamide is added dropwise within a periodof 15 minutes to a suspension of 2.16 g (40 mmol) of sodium methoxide in25 ml of dimethylformamide. The reaction mixture is stirred for afurther 3 hours at room temperature and then concentrated to dryness byevaporation under a high vacuum. Diethyl ether is added to the residueand extraction by shaking is carried out with cold 2N hydrochloric acid.The combined hydrochloric acid extracts are extracted withdichloromethane and the dichloromethane phases are dried over sodiumsulphate and concentrated by evaporation in vacuo. There are obtained4.5 g (44.4%) of4-hydroxy-1-(benzo-1,4-dioxan-2-ylmethyl)-1,2,5,6-tetrahydropyridine-3-carboxylicacid methyl ester hydrochloride or1-(benzo-1,4-dioxan-2-yl-methyl)-4-oxopiperidine-3-carboxylic acidmethyl ester hydrochloride, respectively, which is recrystallised frommethanol/diethyl ether and has a decomposition point of 185°-187°.

N,N-bis(2-methoxycarbonylethyl)-N-(benzo-1,4-dioxan-2-ylmethyl)-aminecan be manufactured, for example, as follows:

7.57 g (88 mmol) of acrylic acid methyl ester are added to a solution of6.61 g (40 mmol) of 2-aminomethylbenzo-1,4-dioxan [J. Augustin et al.,J. Med. Chem. 8, 446 (1965)] in 80 ml of methanol and the whole isstirred for 16 hours at 50°. After cooling, the reaction mixture isconcentrated by evaporation in vacuo. 12.82 g (95%) ofN,N-bis(2-methoxycarbonylethyl)-N-(benzo-1,4-dioxan-2-ylmethyl)-amineare obtained in the form of a reddish oil.

EXAMPLE 10

In a manner analogous to that described in Example 9, by reacting2-aminomethylbenzo-1,4-dioxan with 1 equivalent of acrylic acid methylester, it is possible to manufacture the correspondingN-(2-methoxycarbonylethyl)-N-(benzo-1,4-dioxan-2-ylmethyl)amine whosehydrochloride melts at 153°-155°.

EXAMPLE 11

In a manner analogous to that described in Example 9, it is alsopossible to manufacture4-hydroxy-1-(2-methylbenzo-1,4-dioxan-2-ylmethyl)-1,2,5,6-tetrahydropyridine-3-carboxylicacid methyl ester hydrochloride or1-(2-methylbenzo-1,4-dioxan-2-ylmethyl)-4-oxopiperidine-3-carboxylicacid methyl ester hydrochloride, respectively.

EXAMPLE 12

In a manner analogous to that described in Examples 9 and 10, byreacting 2-(2-aminoethyl)benzo-1,4-dioxan with 1 equivalent of acrylicacid methyl ester, it is possible to manufactureN-[2-(benzo-1,4-dioxan-2-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine andits hydrochloride, and by reacting2-aminomethyl-2-methylbenzo-1,4-dioxan with 1 equivalent of acrylic acidmethyl ester, it is possible to manufactureN-(2-methoxycarbonylethyl)-N-(2-methylbenzo-1,4-dioxan-2-ylmethyl)-amineand its hydrochloride.

EXAMPLE 13

A solution of 52.7 g (0.15 mol) ofN,N-bis(2-methoxycarbonylethyl)-N-[2-(benzo-1,4-dioxan-2-yl)ethyl]-aminein 150 ml of absolute dimethylformamide is added dropwise at roomtemperature while stirring to a suspension of 10.8 g (0.20 mol) ofsodium methoxide in 100 ml of absolute dimethylformamide within a periodof 10 minutes. The reaction mixture is stirred for a further 15 hours atroom temperature and then concentrated to dryness by evaporation under ahigh vacuum. Diethyl ether is added to the resulting residue andextraction is carried out with cold 2N hydrochloric acid. The combinedhydrochloric acid extracts are extracted by shaking withdichloromethane. The dichloromethane phases are dried over sodiumsulphate and concentrated by evaporation in vacuo. There are obtained34.0 g (63.7%) of1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylicacid methyl ester hydrochloride or1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-oxopiperidine-3-carboxylic acidmethyl ester hydrochloride, respectively, which is recrystallised frommethanol/diethyl ether and has a decomposition point of 165°-166°.

N,N-bis(2-methoxycarbonylethyl)-N-[2-(benzo-1,4-dioxan-2-yl)ethyl]-aminecan be manufactured, for example, in the following manner:

34.1 g (0.396 mol) of acrylic acid methyl ester are added at roomtemperature to a solution of 32.25 g (0.18 mol) of2-(2-aminoethyl)-benzo-1,4-dioxan [J. Augustin et al., J. Med. Chem. 8,446 (1965)] in 250 ml of methanol. The reaction mixture is stirred for 6hours at 50° and, after cooling, is concentrated by evaporation invacuo. 57.9 g (91.5%) ofN,N-bis(2-methoxycarbonylethyl)-N-[2-(benzo-1,4-dioxan-2-yl)ethyl]-amineare obtained in the form of a red oil.

EXAMPLE 14

1.25 g of platinum oxide are added to a solution of 12.45 g (35 mmol) of1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylicacid methyl ester hydrochloride or1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-oxopiperidine-3-carboxylic acidmethyl ester hydrochloride, respectively, in 250 ml of methanol and thewhole is hydrogenated at room temperature and at normal pressure. Afterthe theoretically necessary amount of hydrogen has been taken up, thecatalyst is separated off, the filtrate is concentrated by evaporationin vacuo and the oily residue is dissolved in hot acetone. Aftercooling, 4.87 g (38.9%) ofcis-1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-hydroxypiperidine-3-carboxylicacid methyl ester hydrochloride having a melting point of 182°-185°crystallise out.

EXAMPLE 15

At -15° and while stirring, 2.65 g (70 mmol) of sodium borohydride areadded in portions over a period of one hour to a suspension of 12.45 g(35 mmol) of1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylicacid methyl ester hydrochloride or1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-oxopiperidine-3-carboxylic acidmethyl ester hydrochloride, respectively, in 250 ml of methanol.Stirring is continued for a further 4 hours at -10° and then thereaction mixture is concentrated by evaporation in vacuo and taken up inwater/ethyl acetate. The ethyl acetate extracts are washed with water,dried over sodium sulphate and concentrated by evaporation. 11.2 g(100%) of crude product are obtained which are chromatographed on 560 gof silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. 5.41 g(48.2%) oftrans-1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-hydroxypiperidine-3-carboxylicacid methyl ester are obtained in the form of a pale yellow oil. Thetrans-1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-hydroxypiperidine-3-carboxylicacid methyl ester fumarate produced therefrom using fumaric acidcrystallises from methanol/diethyl ether in the form of the hemihydratehaving a melting point of 150°-152°.

EXAMPLE 16

First 19.03 g (125 mmol) of 1,5diazabicyclo[5.4.0]undec-5-ene and then,dropwise and while stirring at 0°-5°, a solution of 3.44 g (30 mmol) ofmethanesulphonyl chloride in 20 ml of toluene are added to a solution of8.03 g (25 mmol) of a mixture of cis- andtrans-1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-hydroxypiperidine-3-carboxylicacid methyl ester in 100 ml of toluene. The whole is then allowed towarm up to room temperature and is stirred for a further 16 hours.Ice-water is then added to the reaction mixture and the organic phase isextracted with 2N hydrochloric acid. The combined hydrochloric acidextracts are rendered alkaline, while cold, with sodium hydroxidesolution (30% strength) and extracted by shaking with dichloromethane.The combined organic phases are washed with water, dried over sodiumsulphate and concentrated by evaporation in vacuo. 5.8 g (76.5%) ofcrude product are obtained and are chromatographed on 300 g of silicagel (0.040-0.063 mm) using toluene/ethyl acetate (1:1) as the eluant.4.13 g (54.5%) of1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylicacid methyl ester are obtained in the form of a yellow oil. The1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylicacid methyl ester hydrochloride produced therefrom using hydrochloricacid in diethyl ether crystallises from methanol/diethyl ether anddecomposes at 205°-206°.

EXAMPLE 17

First 2.1 g (11 mmol) of 1,2,5,6-tetrahydropyridine-3-carboxylic acidethyl ester hydrochloride and then 4.53 g (35 mmol) ofN-ethyl-N,N-diisopropylamine are added to a solution of 3.32 g (10 mmol)of 3-[2-(p-toluenesulphonyloxy)ethyl]-chroman in 50 ml of absolutedimethylformamide. The mixture is stirred for 16 hours at 60° and, aftercooling, is concentrated by evaporation under a high vacuum. Water isadded to the oily residue and extraction is carried out with diethylether. The combined organic phases are extracted with 2N hydrochloricacid. The combined hydrochloric acid extracts are rendered alkaline,while cold, with sodium hydroxide solution (30% strength) and extractedwith dichloromethane. The combined dichloromethane phases are dried oversodium sulphate and concentrated by evaporation in vacuo. 1.65 g (52.3%)of 1-[2-(chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylicacid ethyl ester are obtained in the form of a yellow oil. The1-[2-(chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acidethyl ester hydrochloride produced therefrom using hydrochloric acid indiethyl ether crystallises from acetone/diethyl ether and melts at177°-178°.

EXAMPLE 18

3.4 ml of sulphuric acid (100% strength) are added to a solution of 2.54g (7.5 mmol) of1-[2-(chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acidmethyl ester hydrochloride in 170 ml of absolute ethanol and the wholeis boiled under reflux for 35 hours. After cooling, the reaction mixtureis concentrated by evaporation in vacuo. The residue is dissolved inwater while cold and is extracted with diethyl ether. The aqueous phaseis rendered alkaline, while cold, with sodium hydroxide solution (30%strength) and extracted with dichloromethane. The combineddichloromethane extracts are dried over sodium sulphate and concentratedby evaporation in vacuo. 2.30 g (97.4%) of1-[2-(chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acidethyl ester are obtained in the form of a yellow oil. The1-[2-(chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acidethyl ester hydrochloride produced therefrom using hydrochloric acid indiethyl ether crystallises from acetone/diethyl ether and melts at177°-178°.

EXAMPLE 19

First 3.76 g (24 mmol) of piperidine-3-carboxylic acid ethyl ester andthen 3.1 g (24 mmol) of N-ethyl-N,N-diisopropylamine are added to asolution of 3.98 g (12 mmol) of3-[2-(p-toluenesulphonyloxy)ethyl]chroman in 50 ml of absolutedimethylformamide. The mixture is stirred for 16 hours at 60° and, aftercooling, is concentrated by evaporation under a high vacuum. Water isadded to the oily residue and extraction is carried out with diethylether. The combined organic phases are extracted with 2N hydrochloricacid. The combined hydrochloric acid extracts are rendered alkaline,while cold, with sodium hydroxide solution (30% strength) and extractedwith dichloromethane. The combined dichloromethane phases are dried oversodium sulphate and concentrated by evaporation in vacuo. 3.7 g (97.3%)of 1-[2-(chroman-3-yl)ethyl]-piperidine-3-carboxylic acid ethyl esterare obtained in the form of a yellow oil. The1-[2-(chroman-3-yl)ethyl]-piperidine-3-carboxylic acid ethyl esterhydrochloride produced therefrom using hydrochloric acid in diethylether crystallises from acetone/diethyl ether using 0.18 equivalent ofwater of crystallisation and melts at 140°-143°.

EXAMPLE 20

First 3.76 g (24 mmol) of piperidine-4-carboxylic acid ethyl ester andthen 3.1 g (24 mmol) of N-ethyl-N,N-diisopropylamine are added to asolution of 3.98 g (12 mmol) of3-[2-(p-toluenesulphonyloxy)ethyl]chroman in 50 ml of absolutedimethylformamide. The mixture is stirred for 16 hours at 60° and, aftercooling, is concentrated by evaporation under a high vacuum. Water isadded to the oily residue and extraction by shaking is carried out withdiethyl ether. The combined organic phases are extracted with 2Nhydrochloric acid. The combined hydrochloric acid extracts are renderedalkaline, while cold, with sodium hydroxide solution (30% strength) andextracted with dichloromethane. The combined dichloromethane phases aredried over sodium sulphate and concentrated by evaporation in vacuo. 3.8g (100%) of crude product are obtained which are chromatographed on 200g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. 3.7g (97.3%) of 1-[2-(chroman-3-yl)ethyl]-piperidine-4-carboxylic acidethyl ester are then obtained in the form of a colourless oil. The1-[2-chroman-3-yl)ethyl]-piperidine-4-carboxylic acid ethyl esterhydrochloride produced thereform using hydrochloric acid in diethylether crystallises from ethanol/diethyl ether and melts at 182°-186°.

EXAMPLE 21

First 1.96 g (12.5 mmol) of piperidine-3-carboxylic acid ethyl ester andthen 2.58 g (20 mmol) of N-ethyl-N,N-diisopropylamine are added to asolution of 3.34 g 10 mmol) of2-[2-(p-toluenesulphonyloxy)ethyl]-benzo-1,4-dioxan in 50 ml of absolutedimethylformamide. The mixture is stirred for 16 hours at 60° and, aftercooling, is concentrated by evaporation under a high vacuum. Water isadded to the oily residue and extraction is carried out with diethylether. The combined organic phases are washed with water and extractedwith 2N hydrochloric acid. The combined hydrochloric acid extracts arerendered alkaline, while cold, with sodium hydroxide solution (30%strength) and extracted with dichloromethane. The combineddichloromethane phases are dried over sodium sulphate and concentratedby evaporation in vacuo. 3.82 g (100%) of crude product are obtainedwhich are filtered over 190 g of silica gel (0.040-0.063 mm) using ethylacetate as the eluant. 3.70 g (96.6%) of1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-piperidine-3-carboxylic acid ethylester are then obtained in the form of a pale yellow oil. The1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-piperidine-3-carboxylic acid ethylester hydrochloride produced therefrom using hydrochloric acid indiethyl ether crystallises from ethanol/diethyl ether and melts at162°-165°.

The 2-[2-(p-toluenesulphonyloxy)ethyl]-benzo-1,4-dioxan can be obtained,for example, in the following manner:

Hydrogen chloride is introduced at 5°-10°, while stirring, into asolution of 15.76 g (90 mmol) of 2-cyanomethylbenzo-1,4-dioxan (BE613,211) in 200 ml of absolute methanol until saturation is reached. Thereaction mixture is then thawed to room temperature and is stirred for afurther 16 hours at that temperature. The reaction mixture is thenboiled under reflux for 2 hours. After cooling, the mixture isconcentrated by evaporation in vacuo. Ice-water is added to the oilyresidue and extraction is carried out with diethyl ether. The combinedorganic phases are washed, while cold, with water, saturated sodiumhydrogen carbonate solution and again with water, and then dried oversodium sulphate and concentrated by evaporation in vacuo. 18.2 g (97.3%)of 2-methoxycarbonylmethylbenzo-1,4-dioxan are obtained in the form of apale yellow oil.

At room temperature and while stirring, a solution of 15.61 g (75 mmol)of 2-methoxycarbonylmethylbenzo-1,4-dioxan in 120 ml of absolutetetrahydrofuran is added dropwise within a period of 30 minutes to asuspension of 2.85 g (75 mmol) of lithium aluminium hydride in 120 ml ofabsolute diethyl ether. The reaction mixture is stirred for a further 2hours at room temperature. It is then carefully decomposed with 2.85 mlof water, 2.85 ml of sodium hydroxide solution (15% strength) and 8.55ml of water. The precipitate formed is filtered off with suction and thefiltrate is concentrated by evaporation in vacuo. The oily residue isdissolved in diethyl ether. The solution is washed thoroughly withwater, dried over sodium sulphate and concentrated by evaporation invacuo. 12.37 g (91.6%) of 2-(2-hydroxyethyl)-benzo-1,4-dioxan areobtained in the form of a colourless oil.

12.20 g (64 mmol) of p-toluenesulphonyl chloride are added at roomtemperature and while stirring to a solution of 10.81 g (60 mmol) of2-(2-hydroxyethyl)benzo-1,4-dioxan in 35 ml of absolute pyridine, theslightly exothermic reaction being maintained at room temperature bymeans of an ice bath. The reaction mixture is stirred for a further 3hours at room temperature and then poured onto ice-water. The crystalsformed are filtered off with suction, washed with water and dried invacuo. 15.50 g (77.2%) of2-[2-(p-toluenesulphonyloxy)ethyl]-benzo-1,4-dioxan, which melts at82°-84°, are obtained.

EXAMPLE 22

First 1.96 g (12.5 mmol) of piperidine-4-carboxylic acid ethyl ester andthen 2.58 g (20 mmol) of N-ethyl-N,N-diisopropylamine are added to asolution of 3.34 g (10 mmol) of2-[2-(p-toluenesulphonyloxy)ethyl]-benzo-1,4-dioxan in 50 ml of absolutedimethylformamide. The mixture is stirred for 16 hours at 60° and, aftercooling, is concentrated by evaporation under a high vacuum. Water isadded to the oily residue and extraction is carried out with diethylether. The combined organic phases are washed with water and extractedwith 2N hydrochloric acid. The combined hydrochloric acid extracts arerendered alkaline, while cold, with sodium hydroxide solution (30%strength) and extracted with dichloromethane. The combineddichloromethane phases are dried over sodium sulphate and concentratedby evaporation in vacuo. 3.80 g (99.2%) of crude product are obtainedwhich are filtered over 190 g of silica gel (0.040-0.063 mm) using ethylacetate as the eluant. 3.7 g (96.6%) of1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-piperidine-4-carboxylic acid ethylester are then obtained in the form of a yellow oil. The1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-piperidine-4-carboxylic acid ethylester hydrochloride produced therefrom using hydrochloric acid indiethyl ether crystallises from ethanol/diethyl ether and melts at165°-168°.

EXAMPLE 23

21 ml (42 mmol) of 2N sodium hydroxide solution are added at roomtemperature while stirring to a solution of 2.99 g (10 mmol) ofN-[2-(chroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochloridein 60 ml of methanol. After 5 minutes, 40 ml of water are added to thereaction mixture which is then stirred for 30 minutes at 50°-60°. Aftercooling, the mixture is concentrated by evaporation in vacuo. Theresidue is dissolved in 30 ml of water, and then 10 ml of hydrochloricacid (36% strength) are added and the whole is cooled in an ice bath.The crystals formed are filtered off with suction. 2.5 g (87.5%) ofN-[2-(chroman-3-yl)ethyl]-N-(2-carboxyethyl)-amine hydrochloride areobtained (m.p. 186°-188°).

The N-[2-(chroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)-aminehydrochloride can be manufactured, for example, as described in Example4.

EXAMPLE 24

First 1.57 g (10 mmol) of piperidine-3-carboxylic acid ethyl ester andthen 2.07 g (16 mmol) of N-ethyl-N,N-diisopropylamine are added to asolution of 2.66 g (8 mmol) of 2-[2-(p-toluenesulphonyloxy)ethyl]chromanin 35 ml of absolute dimethylformamide. The mixture is stirred for 16hours at 60° and, after cooling, is concentrated by evaporation under ahigh vacuum. Water is added to the oily residue and extraction iscarried out with diethyl ether. The combined organic phases are washedwith water and extracted with 2N hydrochloric acid. The combinedhydrochloric acid extracts are rendered alkaline, while cold, withsodium hydroxide solution (30% strength) and extracted withdichloromethane. The combined dichloromethane phases are dried oversodium sulphate and concentrated by evaporation in vacuo. 2.28 g (90.1%)of crude product are obtained and are chromatographed on 120 g of silicagel (0.040-0.063 mm) using ethyl acetate as the eluant. 1.82 g (72.2%)of 1-[2-(chroman- 2-yl)ethyl]-piperidine-3-carboxylic acid ethyl esterare then obtained in the form of a yellow oil. The1-[2-(chroman-2-yl)ethyl]-piperidine-3-carboxylic acid ethyl esterhydrochloride produced therefrom using hydrochloric acid in diethylether crystallises from ethanol/diethyl ether and melts at 148°-151°.

2-[2-(p-toluenesulphonyloxy)ethyl]chroman can be manufactured, forexample, in the following manner:

14.2 ml of sulphuric acid (100% strength) are added to a solution of70.34 g (0.39 mol) of 2-carboxychroman in 1400 ml of methanol and thewhole is boiled under reflux for 4 hours. After cooling, the reactionmixture is concentrated by evaporation in vacuo and the residue isdissolved in diethyl ether and washed with water, cold saturated sodiumhydrogen carbonate solution and again with water. The ethereal phase isdried over sodium sulphate and concentrated by evaporation in vacuo.72.8 g (96%) of 2-methoxycarbonylchroman are obtained in the form of apale yellow oil.

At room temperature and while stirring, a solution of 36.4 g (0.19 mol)of 2-methoxycarbonylchroman in 400 ml of absolute tetrahydrofuran isadded dropwise within a period of 1 hour to a suspension of 7.2 g (0.19mol) of lithium aluminium hydride in 400 ml of absolute diethyl ether.After continuing to stir for a further 16 hours at room temperature, thereaction mixture is carefully decomposed with 7.2 ml of water, 7.2 ml ofsodium hydroxide solution (15% strength) and 21.6 ml of water. Theprecipitate formed is filtered off with suction and the filtrate isconcentrated by evaporation in vacuo. The oily residue is dissolved indiethyl ether. The ethereal solution is washed with water, dried oversodium sulphate and concentrated by evaporation in vacuo. 31 g (99.3%)of 2-hydroxymethylchroman are thus obtained in the form of a colourlessoil.

38.16 g (0.2 mol) of p-toluenesulphonyl chloride are added at roomtemperature while stirring to a solution of 31 g (0.189 mol) of2-hydroxymethylchroman in 110 ml of absolute pyridine, the slightlyexothermic reaction being maintained at room temperature by means of anice bath. The reaction mixture is stirred for a further 3 hours at roomtemperature and then poured onto ice-water. The oil which separates outis removed by decanting the aqueous phase, dissolved in diethyl etherand washed with ice-cold 2N hydrochloric acid and ice-water. Theethereal phases are dried over sodium sulphate and concentrated byevaporation in vacuo. 58.15 g (96.6%) of2-(p-toluenesulphonyloxymethyl)chroman are obtained in the form of acolourless oil.

10.6 g (0.216 mol) of sodium cyanide are added to a solution of 57.31 g(0.18 mol) of 2-(p-toluenesulphonyloxymethyl)chroman in 800 ml ofabsolute dimethylformamide and the whole is heated, while stirring, to60°. After 10 hours, ice-water is added to the reaction mixture andextraction is carried out with diethyl ether. The combined etherealphases are washed thoroughly with water, dried over sodium sulphate andconcentrated by evaporation in vacuo. 30.0 g (96.2%) of crude productare obtained and are chromatographed on 1000 g of silica gel(0.040-0.063 mm) using toluene as the eluant. 18.16 g (58.2%) of2-cyanomethylchroman are thus obtained in the form of a yellow oil.

Hydrogen chloride gas is introduced at 5°-10° into a solution of 17.32 g(0.1 mol) of 2-cyanomethylchroman in 200 ml of absolute methanol untilsaturation is reached. The reaction mixture is then thawed to roomtemperature and is stirred for a further 16 hours at that temperature.The reaction mixture is then boiled under reflux for 2 hours. It is thencooled and the mixture is concentrated by evaporation in vacuo.Ice-water is added to the residue and extraction is carried out withdiethyl ether. The combined organic phases are washed, while cold, withwater, sodium hydrogen carbonate solution and again with water, and thendried over sodium sulphate and concentrated by evaporation in vacuo.18.58 g (90.1%) of crude product are obtained and are filtered over 460g of silica gel (0.040-0.063 mm) using toluene as the eluant. 17.80 g(86.3%) of 2-methoxycarbonylmethylchroman are obtained in the form of apale yellow oil.

At room temperature and while stirring, a solution of 16.91 g (82 mmol)of 2-methoxycarbonylmethylchroman in 150 ml of absolute tetrahydrofuranis added dropwise within a period of 30 minutes to a suspension of 3.11g (82 mmol) of lithium aluminium hydride in 150 ml of absolute diethylether. Stirring is continued for a further 16 hours at room temperatureand then the whole is carefully decomposed with 3.1 ml of water, 3.1 mlof sodium hydroxide solution (15% strength) and 9.3 ml of water. Theprecipitate formed is filtered off with suction and the filtrate isconcentrated by evaporation in vacuo. The oily residue is dissolved indiethyl ether. The ethereal solution is washed with water, dried oversodium sulphate and concentrated by evaporation in vacuo. 14.36 g(98.3%) of 2-(2-hydroxyethyl)chroman are obtained in the form of acolourless oil.

15.73 g (82.5 mmol) of p-toluenesulphonyl chloride are added at roomtemperature while stirring to a solution of 13.36 g (75 mmol) of2-(2-hydroxyethyl)chroman in 90 ml of absolute pyridine, the slightlyexothermic reaction being maintained at room temperature by means of anice bath. After stirring for a further 3 hours at room temperature, thereaction mixture is poured onto ice-water. The crystals formed arefiltered off with suction, washed with water and dried in vacuo. Thereare obtained 8.68 g (34.7%) of 2-[2-(p-toluenesulphonyloxy)ethyl]chromanwhich melts at 57°-59°.

EXAMPLE 25

First 1.57 g (10 mmol) of piperidine-4-carboxylic acid ethyl ester andthen 2.07 g (16 mmol) of N-ethyl-N,N-diisopropylamine are added to asolution of 2.66 g (8 mmol) of 2-[2-(p-toluenesulphonyloxy)ethyl]chromanin 35 ml of absolute dimethylformamide. The mixture is stirred for 16hours at 60° and then, after cooling, is concentrated by evaporationunder a high vacuum. Water is added to the oily residue and extractionis carried out with diethyl ether. The combined organic phases arewashed with water and extracted with 2N hydrochloric acid. The combinedhydrochloric acid extracts are rendered alkaline, while cold, withsodium hydroxide solution (30% strength) and extracted withdichloromethane. The combined dichloromethane phases are dried oversodium sulphate and concentrated by evaporation in vacuo. 2.17 g (85.7%)of crude product are obtained and are chromatographed on 110 g of silicagel (0.040-0.063 mm) using ethyl acetate as the eluant. 1.90 g (75.1%)of 1-[2 -(chroman-2-yl)ethyl]-piperidine-4-carboxylic acid ethyl esterare thus obtained in the form of a yellow oil. The1-[2-(chroman-2-yl)ethyl]-piperidine-4-carboxylic acid ethyl esterhydrochloride produced therefrom using hydrochloric acid in diethylether crystallises from ethanol/diethyl ether and melts at 190°-192°.

EXAMPLE 26

3.01 g (35 mmol) of acrylic acid methyl ester are added at 0°-5°, whilestirring, to a solution of 6.2 g (35 mmol) of 2-(2-aminoethyl)chroman in200 ml of methanol. Stirring is continued for a further 16 hours at0°-5° and the mixture is then concentrated by evaporation in vacuo. 8.76g (95.2%) of crude product are obtained and are chromatographed on 250 gof silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. 5.10 g(55.4%) of N-[2-(chroman-2-yl)ethyl]-N-(2-methoxycarbonylethyl)-amineare thus obtained in the form of a yellow oil. TheN-[2-(chroman-2-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochlorideproduced therefrom using hydrochloric acid in diethyl ether crystallisesfrom methanol/diethyl ether and melts at 152°-153°.

2-(2-aminoethyl)chroman can be manufactured, for example, in thefollowing manner:

First, at room temperature and while stirring, 2.2 g (16.5 mmol) ofaluminium chloride in 70 ml of absolute diethyl ether are added dropwiseto a suspension of 3.8 g (100 mmol) of lithium aluminium hydride in 150ml of absolute diethyl ether. Then 8.66 g (50 mmol) of2-cyanomethylchroman in 70 ml of absolute tetrahydrofuran are addeddropwise within a period of 20 minutes. The reaction mixture is stirredfor a further 16 hours at room temperature and then carefully decomposedwith 3.8 ml of water, 3.8 ml of sodium hydroxide solution (15% strength)and 11.4 ml of water. The precipitate formed is filtered off withsuction and the filtrate is concentrated by evaporation in vacuo. Theoily residue is dissolved in diethyl ether. The ethereal phase is washedwith water, dried over sodium sulphate and concentrated by evaporation.8.75 g (98.8%) of 2-(2-aminoethyl)chroman are obtained in the form of acolourless oil.

EXAMPLE 27

1.5 ml of concentrated hydrochloric acid are added to a solution of 4.81g (0.015 mol) of1-[2-(chroman-3-yl)ethyl]-3-cyano-4-hydroxy-1,2,5,6-tetrahydropyridinehydrochloride or 1-[2-(chroman-3-yl)ethyl]-3-cyano-4-oxopiperidinehydrochloride, respectively, in 100 ml of methanol (95% strength) andthe whole is boiled under reflux for 15 hours. After cooling, thereaction mixture is concentrated to a volume of approximately 30 mlunder reduced pressure and the solution is poured into a mixture of 80ml of 5N hydrochloric acid and 20 ml of toluene, whereupon, whilestirring and cooling,1-[2-(chroman-3-yl)ethyl]-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylicacid methyl ester hydrochloride or1-[2-(chroman-3-yl)ethyl]-4-oxopiperidine-3-carboxylic acid methyl esterhydrochloride, respectively, having a melting point of 175°-177°(decomposition) crystallises out.

The1-[2-(chroman-3-yl)ethyl]-3-cyano-4-hydroxy-1,2,5,6-tetrahydropyridinehydrochloride or 1-[2-(chroman-3-yl)ethyl]-3-cyano-4-oxopiperidinehydrochloride, respectively, can be manufactured, for example, in thefollowing manner:

30 g (0.1 mol) ofN-[2-(chroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochlorideare dissolved in 100 ml of methanol, and then 10.5 g (0.1 mol) oftriethylamine and 5.84 g (0.11 mol) of acrylonitrile are added to thesolution and the whole is stirred for 15 hours at room temperature. Thereaction mixture is then concentrated under a water-jet vacuum, theresidue is taken up in diethyl ether and the ethereal solution is washedneutral with ice-water. The ethereal phase is dried over potassiumcarbonate and concentrated by evaporation.N-[2-(chroman-3-yl)ethyl]-N-(2-cyanoethyl)-N-(2-methoxycarbonylethyl)-amineis thus obtained in the form of a yellow oil.

A solution of 13.07 g (41.3 mmol) ofN-[2-(chroman-3-yl)ethyl]-N-(2-cyanoethyl)-N-(2-methoxycarbonylethyl)-aminein 200 ml of tetrahydrofuran is added dropwise under a nitrogenatmosphere to a suspension of 5.73 g of sodium hydride (55% suspensionin mineral oil) in 100 ml of tetrahydrofuran and the whole is stirredfor 16 hours at room temperature. After adding 70 ml of 2N sulphuricacid, a yellow solution is obtained. 300 ml of diethyl ether and 100 mlof water are added thereto to form two phases. The aqueous phase isextracted three times with 100 ml of diethyl ether each time. Thecombined organic phases are dried over sodium sulphate, concentrated toapproximately 100 ml under reduced pressure and then poured into amixture of 80 ml of 5N hydrochloric acid and 20 ml of toluene,whereupon, while stirring and cooling,1-[2-(chroman-3-yl)ethyl]-3-cyano-4-hydroxy-1,2,5,6-tetrahydropyridinehydrochloride or 1-[2-(chroman-3-yl)ethyl]-3-cyano-4-oxopiperidinehydrochloride, respectively, crystallises out.

EXAMPLE 28

17.4 ml of n-butyllithium in hexane are added at 0°-5° to a solution of2.81 g of diisopropylamine in 30 ml of dry tetrahydrofuran. The whole isstirred for 30 minutes at room temperature, then cooled to -15° and asolution of 6.24 g (25 mmol) of1-[2-(chroman-3-yl)ethyl]-4-oxopiperidine in 30 ml of tetrahydrofuran isadded. After 15 minutes, a solution of 3.05 g (28 mmol) ofchlorotrimethylsilane in 15 ml of tetrahydrofuran is added dropwise. Thewhole is stirred overnight at room temperature, the solution is filteredand the filtrate is concentrated to dryness by evaporation under reducedpressure.1-[2-(chroman-3-yl)ethyl]-4-trimethylsilyloxy-1,2,5,6-tetrahydropyridineis thus obtained in the form of a pale yellow oil. 6.63 g (20 mmol) ofthe1-[2-(chroman-3-yl)ethyl]-4-trimethylsilyloxy-1,2,5,6-tetrahydropyridineobtained are dissolved in 50 ml of dichloromethane and the solution isadded dropwise to a solution, cooled to 0°, of 2.3 g (24 mmol) ofchloroformic acid methyl ester and 60 mg (2.4 mmol) of anhydrous zincbromide in 50 ml of absolute dichloromethane. After warming up to roomtemperature, the reaction solution is stirred for one hour and thenpoured onto 150 ml of saturated sodium hydrogen carbonate solution.Extraction is carried out with dichloromethane, and the combined organicphases are dried over sodium sulphate and then concentrated byevaporation. The residue is dissolved in 70 ml of ethanol and thesolution is acidified with ethanolic hydrochloric acid. After addingdiethyl ether and after cooling,1-[2-(chroman-3-yl)ethyl]-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylicacid methyl ester hydrochloride or1-[2-(chroman-3-yl)ethyl]-4-oxopiperidine-3-carboxylic acid methyl esterhydrochloride, respectively, having a melting point of 175°-177°crystallises out.

The 1-[2-(chroman-3-yl)ethyl]-4-oxopiperidine can be manufactured, forexample, in the following manner:

First 8.45 g (55 mmol) of piperidone hydrochloride monohydrate and then22.62 g (175 mmol) of N-ethyl-N,N-diisopropylamine are added to asolution of 16.62 g (50 mmol) of3-[2-(p-toluenesulphonyloxy)ethyl]chroman in 100 ml ofdimethylformamide. The mixture is stirred for 18 hours at 80° and, aftercooling, is concentrated to dryness by evaporation under reducedpressure. The residue is dissolved in diethyl ether and washed withwater. The organic phase is separated off and extracted with 2Nhydrochloric acid. The hydrochloric acid extracts are combined, renderedalkaline, while cold, with concentrated sodium hydroxide solution andextracted with dichloromethane. The dichloromethane phases are combined,dried over sodium sulphate and concentrated to dryness by evaporationunder reduced pressure. A dark brown resin is obtained which is purifiedby chromatography on 350 g of silica gel (0.040-0.063 mm) usingtoluene/ethyl acetate (1:1) as the eluant.1-[2-(chroman-3-yl)ethyl]-4-oxopiperidine is obtained in the form of apale yellow oil.

EXAMPLE 29

A solution of 2.7 g (25 mmol) of benzyl alcohol in 25 ml oftetrahydrofuran is added to a suspension of 1.2 g of sodium hydride (50%suspension in mineral oil) in 25 ml of dry tetrahydrofuran and, when theevolution of gas has subsided, the whole is heated under reflux for 30minutes. After cooling, a solution of 8.5 g (25 mmol) of1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylicacid methyl ester in 50 ml of tetrahydrofuran is added dropwise and thewhole is heated under reflux again for 5 hours. After cooling, thesolvent is removed. A mixture of cis- andtrans-1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-benzyloxypiperidine-3-carboxylicacid methyl ester is obtained in the form of an oil.

EXAMPLE 30

At -10° and while stirring, 1.41 g of sodium borohydride are introducedwithin a period of 90 minutes into a suspension of 8.45 g (18 mmol) of1-[2-(chroman-3-yl)ethyl]-3-methoxycarbonylpyridiniump-toluenesulphonate in 43 ml of methanol. Stirring is continued for 1hour at 0° and for 2 hours at room temperature and then 50 ml of waterare added to the reaction mixture and extraction by shaking is carriedout twice with 100 ml of dichloromethane each time. The dichloromethanephases are combined, dried over magnesium sulphate and concentrated todryness by evaporation. The crude product is purified by chromatographyon 150 g of silica gel (0.063-0.2 mm) using ethyl acetate as the eluant.The main eluate, which is concentrated by evaporation, is treated withethereal hydrochloric acid to yield1-[2-(chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acidmethyl ester hydrochloride having a melting point of 175°-177°.

The 1-[2-(chroman-3-yl)ethyl]-3-methoxycarbonylpyridiniump-toluenesulphonate can be manufactured, for example, in the followingmanner:

16.6 g (50 mmol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman and 9.3 g(67.5 mmol) of pyridine-3-carboxylic acid methyl ester are suspended in50 ml of butan-2-one and the suspension is boiled for 72 hours whilestirring. It is cooled, the reaction mixture is concentrated underreduced pressure, and1-[2-(chroman-3-yl)ethyl]-3-methoxycarbonylpyridiniump-toluenesulphonate is thus obtained in the form of a white foam.

EXAMPLE 31

33.2 g (0.1 mol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman, 14.0 g ofN-(2-methoxycarbonylethyl)-amine hydrochloride and 39 g ofN-ethyl-N,N-diisopropylamine are dissolved under nitrogen in 750 ml ofdimethylformamide and the solution is stirred for 16 hours at roomtemperature. The reaction mixture is subsequently concentrated toapproximately 200 ml under reduced pressure, 500 ml of water are thenadded and the whole is extracted by shaking three times with 150 ml ofdichloromethane each time. The combined organic phases are dried oversodium sulphate and concentrated to dryness by evaporation. By addingethanolic hydrochloric acid and cooling,N-[2-(chroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochloridehaving a melting point of 190°-192° is obtained.

EXAMPLE 32

6 ml of concentrated hydrochloric acid are added to a solution of 11.5 g(0.05 mmol) of N-[2-(chroman-3-yl)ethyl]-N-(2-cyanoethyl)-amine in 100ml of methanol. The reaction mixture is boiled under reflux for 15hours. After cooling, the solvent is removed under reduced pressure andthe residue is crystallised from methanol/acetone. Afterrecrystallisation from methanol/acetone,N-[2-(chroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochloridehaving a melting point of 190°-192° is obtained (yield: 82%).

The N-[2-(chroman-3-yl)ethyl]-N-(2-cyanoethyl)-amine can bemanufactured, for example, in the following manner:

17.7 g (0.1 mol) of 3-(2-aminoethyl)chroman are dissolved in 100 ml ofmethanol, and then 10.5 g (0.1 mol) of triethylamine and 5.84 g (0.11mol) of acrylonitrile are added to the solution. The reaction mixture isstirred for 15 hours at room temperature and then concentrated under awater-jet vacuum. The residue is taken up in diethyl ether and washedneutral with ice-water. The ethereal phase is dried over potassiumcarbonate and concentrated by evaporation.N-[2-(chroman-3-yl)ethyl]-N-(2-cyanoethyl)-amine is thus obtained in theform of a pale yellow oil.

EXAMPLE 33

5.2 g of a mixture of cis- andtrans-1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-benzyloxypiperidine-3-carboxylicacid methyl ester are dissolved in 100 ml of methanol, and then 2 g ofpalladium-on-carbon (10%) are added and the whole is hydrogenated in aParr apparatus for 12 hours at room temperature. The reaction mixture isthen filtered over diatomaceous earth and the filtrate is concentratedto dryness by evaporation. The crude oily residue is chromatographed onsilica gel using toluene/ethyl acetate (9:1) as the eluant. First thetrans-1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-hydroxypiperidine-3-carboxylicacid methyl ester and then thecis-1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-hydroxypiperidine-3-carboxylicacid methyl ester is eluted. In each case the purified fractions arecombined and concentrated by evaporation. The residue that contains thetrans product is treated with fumaric acid in methanol/diethyl ether andthus yieldstrans-1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-hydroxypiperidine-3-carboxylicacid methyl ester fumarate which crystallises out in the form of thehemihydrate and melts at 150°-152°. The residue that contains the cisproduct is treated with ethereal hydrochloric acid and thus yieldscis-1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-hydroxypiperidine-3-carboxylicacid methyl ester hydrochloride which has a melting point of 182°-185°.

EXAMPLE 34

6.8 g (20 mmol) of a mixture of cis-andtrans-1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-chloropiperidine-3-carboxylicacid methyl ester are dissolved in 20 ml of methanol. 40 ml (140 mmol)of a 3.5N solution of ammonia in methanol are added dropwise at roomtemperature. The mixture is left to stand at room temperature for 24hours. The solvent is then removed under reduced pressure. The resultingresidue is dissolved in dichloromethane, the solution is extracted byshaking with 2N hydrochloric acid and the acidic aqueous phase isseparated off, rendered alkaline with sodium hydrogen carbonate andextracted with diethyl ether/dichloromethane (2:1). The organic extractsare washed with saturated sodium chloride solution, dried over magnesiumsulphate and freed of the solvent under reduced pressure. The resultingresidue is chromatographed on basic silica gel usingdichloromethane/methanol (99:1) as the eluant. The eluates are combinedand concentrated to dryness by evaporation. The oily residue consists ofpure 4-amino-1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-piperidine-3-carboxylicacid amide (cis/trans mixture).

A mixture of cis- andtrans-1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-chloropiperidine-3-carboxylicacid methyl ester can be obtained, for example, as follows:

9.7 g (30 mmol) of a mixture of cis- andtrans-1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-hydroxypiperidine-3-carboxylicacid methyl ester (for manufacture see Example 33) and 3.6 g (36 mmol)of triethylamine are dissolved in 100 ml of dichloromethane. 3.92 g (33mmol) of thionyl chloride are added dropwise while stirring at roomtemperature. The mixture is stirred for 4 hours at room temperature. Thetriethylamine hydrochloride formed is then filtered off and thefiltrate, while cold, is extracted by shaking with saturated sodiumhydrogen carbonate solution. The organic phase is washed with saturatedsodium chloride solution, dried over magnesium sulphate and freed of thesolvent under reduced pressure. The resulting mixture of cis- andtrans-1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-chloropiperidine-3-carboxylicacid methyl ester is used further in the crude state.

EXAMPLE 35

At room temperature and while stirring, a solution of 11.94 g (30 mmol)ofN-(3-ethoxycarbonylpropyl)-N-(2-bromoethyl)-N-[2-(chroman-3-yl)ethyl]-aminein 40 ml of absolute dimethylformamide is added dropwise within a periodof 20 minutes to a suspension of 2.72 g (40 mmol) of sodium ethoxide in30 ml of dimethylformamide. The reaction mixture is stirred for 16 hoursat room temperature and then concentrated to dryness by evaporationunder a high vacuum. Diethyl ether is added to the residue andextraction is carried out with cold 2N hydrochloric acid. The combinedhydrochloric acid extracts are extracted by shaking with dichloromethaneand the dichloromethane phases are dried over sodium sulphate andconcentrated by evaporation in vacuo. The crude product is obtained asthe residue and is chromatographed on 500 g of silica gel (0.040-0.063mm) using ethyl acetate as the eluant. The eluate is concentrated byevaporation to yield 1-[2-(chroman-3-yl)ethyl]-piperidine-4-carboxylicacid ethyl ester in the form of a colourless oil. The1-[2-(chroman-3-yl)ethyl]-piperidine-4-carboxylic acid ethyl esterhydrochloride produced therefrom using hydrochloric acid in diethylether crystallises from ethanol/diethyl ether and melts at 182°-186°.

TheN-(3-ethoxycarbonylpropyl)-N-(2-bromoethyl)-N-[2-(chroman-3-yl)ethyl]-aminecan be manufactured, for example, in the following manner:

17.7 g (0.1 mol) of 3-(2-aminoethyl)chroman are dissolved in 100 ml ofmethanol, and then 10.5 g (0.1 mol) of triethylamine and 19.5 g (0.1mol) of 4-bromobutyric acid ethyl ester are added to the solution. Thereaction mixture is stirred for 15 hours at room temperature and is thenconcentrated under a water-jet vacuum. The residue is taken up indiethyl ether and washed neutral with ice-water. The ethereal phase isdried over potassium carbonate and concentrated by evaporation. OilyN-(3-ethoxycarbonylpropyl)-N-[2-(chroman-3-yl)ethyl]-amine is thusobtained and can be used further in crude form.

29.1 g (0.1 mol) ofN-(3-ethoxycarbonylpropyl)-N-[2-(chroman-3-yl)ethyl]-amine are dissolvedin 200 ml of methanol, and then 10.5 g (0.1 mol) of triethylamine and18.8 g (0.1 mol) of 1,2-dibromoethane are added to the solution. Thereaction mixture is stirred for 16 hours at room temperature and thenconcentrated under a water-jet vacuum. The residue is taken up indiethyl ether and washed neutral with ice-water. The ethereal phase isdried over potassium carbonate and concentrated by evaporation.N-(3-ethoxycarbonylpropyl)-N-(2-bromoethyl)-N-[2-(chroman-3-yl)ethyl]-amineis thus obtained in the form of an oil which can be used further in thecrude state.

EXAMPLE 36

In a manner analogous to that described in Examples 4, 5, 10, 12, 23,26, 31 and 32, it is also possible to obtainN-[2-(chroman-4-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine and itshydrochloride.

EXAMPLE 37

In a manner analogous to that described in Examples 1 to 3, 6 to 9, 11,13 to 22, 24, 25, 27 to 30 and 33 to 35 it is also possible to obtain1-[2-(chroman-4-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acidmethyl ester and its hydrochloride and1-[2-(chroman-4-yl)ethyl]-piperidine-3-carboxylic acid ethyl ester andits hydrochloride.

EXAMPLE 38

First 5.55 g (25 mmol) of 1,2,5,6-tetrahydropyridine-3-carboxylic acidmethyl ester hydrobromide (guvacoline hydrobromide) and then 11.31 g(87.5 mmol) of N-ethyl-N,N-diisopropyl-amine are added to a solution of9 g (25 mmol) of 2,2-dimethyl-3-[2-(4-toluenesulfonyloxy)-ethyl]-chromanin 100 ml of N,N-dimethylformamide. The solution is stirred for 15 hoursat 60° and then concentrated by evaporation under a high vacuum. Wateris added to the residue and extraction is carried out with diethylether. The combined organic phases are washed with water and extractedwith 2N hydrochloric acid. The combined hydrochloric acid extracts arerendered alkaline with sodium hydroxide solution (30%) while cooling andextracted with dichloromethane. The combined dichloromethane phases aredried over sodium sulfate and concentrated by evaporation in vacuo,yielding 5.52 g (67% of theoretical yield) of1-[2-(2,2-dimethylchroman-3-yl)-ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylicacid methyl ester in the form of a light-yellow oil. 1-[2-(2,2-dimethylchroman-3-yl)-ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylicacid methyl ester hydrochloride, prepared therefrom with hydrochloricacid in diethyl ether, crystallises from methanol/diethyl ether andmelts at 196°-197°.

2,2-dimethyl-3-[2-(4-toluenesulfonyloxy)-ethyl]-chroman can be obtained,for example, as follows:

25 g (0.6 mol) of sodium hydride dispersion (57% in mineral oil) aresubstantially freed of mineral oil by repeated washing with n-hexane andare then covered with a layer of 500 ml of dried tetrahydrofuran. Undera nitrogen atmosphere and while cooling in an ice bath, 134 g (0.6 mol)of phosphonoacetic acid triethyl ester of formula (H₅ C₂ O)₂ P(═O)CH₂C(═O)OC₂ H₅ are added dropwise thereto within a period of 1 hour. Themixture is stirred for a further 1 hour at 0°. To the homogeneoussolution there is then added dropwise within a period of 30 minutes asolution of 88.57 g (0.5 mol) of 2,2-dimethyl-3-oxo-chroman [F. Camps etal., J. Heterocyclic Chem. 22, 1421 (1985)] in 300 ml oftetrahydrofuran. The mixture is stirred overnight at room temperature.The solution is then concentrated to approximately 350 ml in vacuo andpoured onto 3 liters of ice-cold phosphate buffer solution (pH=6). Themixture is extracted with diethyl ether. The combined organic phases arewashed with water and dried over sodium sulfate and then concentrated byevaporation in vacuo. The yellow residue is chromatographed on 4 kg ofsilica gel (0.040-0.063 mm) with toluene as eluant, yielding 60.3 g (49%of the theoretical yield) of3-ethoxycarbonylmethyl-2,2-dimethyl-2H-chromene in the form of alight-yellow oil.

3 g of palladium-on-carbon (5%) are added to a solution of 59.1 g (0.24mol) of 3-ethoxycarbonylmethyl-2,2-dimethyl-2H-chromene in 400 ml ofabsolute ethanol and the mixture is hydrogenated in a PARR apparatus atroom temperature for 2 hours. The reaction mixture is then filtered overdiatomaceous earth. The filtrate is concentrated to dryness byevaporation. The oily residue consists of pure3-ethoxycarbonylmethyl-2,2-dimethyl-chroman.

While cooling with ice, a solution of 50 g (0.2 mol) of3-ethoxycarbonylmethyl-2,2-dimethyl-chroman in 250 ml of absolutediethyl ether is added dropwise within a period of 1 hour to asuspension of 7.6 g (0.2 mol) of lithium aluminium hydride in 200 ml ofabsolute diethyl ether. The reaction mixture is then stirred for 3 hoursat room temperature and then carefully decomposed with 7.5 ml of water,7.5 ml of sodium hydroxide solution (15%) and 23 ml of water. Theresulting precipitate is filtered off. The filtrate is dried over sodiumsulfate and concentrated by evaporation in vacuo, yielding 39.5 g (95%of the theoretical yield) of 2,2-dimethyl-3-(2-hydroxyethyl)-chroman inthe form of a colourless oil.

38 g (0.2 mol) of 4-toluenesulfonyl chloride are added at roomtemperature, while stirring, to a solution of 37.1 g (0.18 mol) of2,2-dimethyl-3-(2-hydroxyethyl)-chroman in 150 ml of pyridine, theslightly exothermic reaction being maintained at room temperature withan ice bath. The mixture is then stirred for 4 hours at roomtemperature. The reaction mixture is then poured onto ice-water andextracted with diethyl ether. The combined ethereal phases are washedthree times using 150 ml of citric acid solution (5%) each time andthree times using 150 ml of water each time, then dried over sodiumsulfate and concentrated by evaporation, yielding 59.1 g (89% of thetheoretical yield) of2,2-dimethyl-3-[2-(4-toluenesulfonyloxy)-ethyl]-chroman in the form of ayellow oil which is further used in that form.

EXAMPLE 39

While stirring at room temperature, 0.87 g (18 mmol) of sodium hydridedispersion in mineral oil (50%) are introduced within a period of 30minutes to a solution of 5.66 g (15 mmol) ofN-[2-(2,2-dimethylchroman-3-yl)-ethyl]-N,N-bis(2-methoxycarbonylethyl)-aminein 50 ml of absolute N,N-dimethylformamide. The reaction mixture isstirred at room temperature for 1 hour and then concentrated to drynessby evaporation under a high vacuum. Diethyl ether is added to theresidue and extraction is carried out with cold 2N hydrochloric acid.The combined hydrochloric acid extracts are extracted by shaking withdichloromethane and the dichloromethane phases are dried over sodiumsulfate and concentrated by evaporation in vacuo, yielding 1.95 g (34%of the theoretical yield) of1-[2-(2,2-dimethylchroman-3-yl)-ethyl]-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylicacid methyl ester hydrochloride or1-[2-(2,2-dimethylchroman-3-yl)-ethyl]-4-oxo-piperidine-3-carboxylicacid methyl ester hydrochloride, respectively, which afterrecrystallisation from methanol/diethyl ether has a decomposition rangeof 168°-170°.

N-[2-(2,2-dimethylchroman-3-yl)-ethyl]-N,N-bis(2-methoxycarbonylethyl)-aminecan be prepared, for example, in the following manner:

A solution of 3.9 g (60 mmol) of sodium azide in 10 ml of water is addedto a solution of 14.4 g (40 mmol) of2,2-dimethyl-3-[2-(4-toluenesulfonyloxy)-ethyl]-chroman (prepared asdescribed in Example 38) in 200 ml of ethanol. The mixture is boiledunder reflux for 18 hours. After cooling, the ethanol is evaporated offin vacuo, water is added to the residue and extraction is carried outwith dichloromethane. The dichloromethane phase is washed with water,dried over sodium sulfate and concentrated by evaporation, yielding 8.7g (94% of the theoretical yield) of3-(2-azidoethyl)-2,2-dimethyl-chroman in the form of a yellow oil.

A solution of 6.94 g (30 mmol) of 3-(2-azidoethyl)-2,2-dimethyl-chromanin 100 ml of absolute tetrahydrofuran is added dropwise at roomtemperature, within a period of 1 hour, to a suspension, stirred in anitrogen atmosphere, of 1.14 g (30 mmol) of lithium aluminium hydride in100 ml of absolute diethyl ether. After stirring for a further 2 hours,the reaction mixture is hydrolysed with 1.14 ml of water, 1.14 ml ofsodium hydroxide solucion (15%) and 3.4 ml of water. The resultingprecipitate is filtered off with suction and the filtrate is completelyconcentrated by evaporation in vacuo. The oil obtained as residue isdissolved in 150 ml of diethyl ether and the solution is extracted with2N hydrochloric acid. The combined hydrochloric acid extracts arerendered alkaline with concentrated sodium hydroxide solution whilecooling with ice and extracted with dichloromethane. The combinedorganic phases are dried over sodium sulfate and concentrated byevaporation in vacuo, yielding 5.6 g (91% of the theoretical yield) of3-(2-aminoethyl)-2,2-dimethyl-chroman in the form of a yellow oil ofwhich the hydrochloride melts, with decomposition, at 245°-248°.

4.74 g (55 mmol) of acrylic acid methyl ester are added at roomtemperature to a solution of 5.13 g (25 mmol) of3-(2-aminoethyl)-2,2-dimethyl-chroman in 50 ml of methanol. The mixtureis stirred for 16 hours at room temperature and then concentrated byevaporation in vacuo, yielding 9.43 g (100% of the theoretical yield) ofN-[2-(2,2-dimethylchroman-3-yl)-ethyl]-N,N-bis(2-methoxycarbonylethyl)-aminein the form of a light-yellow oil which is further used in that form.

EXAMPLE 40

While cooling with ice, a solution of 1.3 g (15 mmol) of acrylic acidmethyl ester in 25 ml of methanol is added dropwise within a period of15 minutes to a solution of 3.08 g (15 mmol) of3-(2-amino-ethyl)-2,2-dimethyl-chroman (prepared as described in Example39) in 75 ml of methanol. The reaction mixture is then stirred at 0° for6 hours and then concentrated by evaporation in vacuo. The oily residueis chromatographed on 300 g of silica gel (0.040-0.063 mm) with ethylacetate as eluant, yielding 2.75 g (63% of the theoretical yield) ofN-[2-(2,2-dimethylchroman-3-yl)-ethyl]-N-(2-methoxycarbonylethyl)-aminein the form of a light-yellow oil of which the hydrochloride melts at132°-134°.

EXAMPLE 41

15 ml of a 5N solution of ammonia in methanol are added to a solution of2.91 g (10 mmol) ofN-[2-(2,2-dimethylchroman-3-yl)-ethyl]-N-(2-methoxycarbonylethyl)-amine(prepared as described in Example 40) in 20 ml of methanol and thereaction mixture is left to react in a closed vessel for 6 days at roomtemperature. The mixture is then concentrated by evaporation andN-(2-aminocarbonylethyl)-N-[2-(2,2-dimethylchroman-3-yl)-ethyl]-aminehydrochloride, having a melting range of 194°-196°, is prepared from theresidue with methanolic hydrochloric acid.

EXAMPLE 42

While stirring at a temperature of from 0° to 5°, a solution of 0.86 g(9.9 mmol) of acrylic acid methyl ester in 10 ml of methanol is addeddropwise within a period of 15 minutes to a solution of 2.23 g (10 mmol)of 3-(2-aminoethyl)-2,2-dimethyl-6-fluoro-chroman in 50 ml of methanol.The reaction mixture is then stirred for 16 hours at from 0° to 5° andthen concentrated by evaporation in vacuo. The oily residue ischromatographed on 200 g of silica gel (0.040-0.063 mm) with ethylacetate as eluant, yielding 1.9 g (61.4% of the theoretical yield) ofN-[2-(2,2-dimethyl-6-fluoro-chroman-3-yl)-ethyl]-N-(2-methoxycarbonylethyl)-aminein the form of a light-yellow oil. TheN-[2-(2,2-dimethyl-6-fluoro-chroman-3-yl)-ethyl]-N-(2-methoxycarbonylethyl)-aminehydrochloride, prepared therefrom with hydrochloric acid in diethylether, crystallises from acetone/diethyl ether and melts at 129°-131°.

3-(2-aminoethyl)-2,2-dimethyl-6-fluoro-chroman can be prepared, forexample, as follows:

83.1 g (0.2 mol) of potassium carbonate are added, while stirring, to asolution of 28.0 g (0.2 mol) of 5-fluoro-2-hydroxy-benzaldehyde[prepared according to Y. Suzuki and H. Takahashi, Chem. Pharm. Bull.31, 1751 (1983)] in 500 ml of N,N-dimethylformamide. 36.3 g (0.2 mol) of3,3-dimethylacrylic acid ethyl ester are added to the resulting viscoussuspension. The reaction mixture is then stirred for 16 hours at 150°and, after cooling to room temperature, concentrated by evaporation invacuo. Water is added to the resulting solid residue and the aqueousmixture is extracted with diethyl ether. The combined ethereal phasesare washed in succession with water, 2N hydrochloric acid, 2N sodiumhydroxide solution and again with water, dried over sodium sulfate andconcentrated by evaporation in vacuo. The resulting oily residue ischromatographed on 1000 g of silica gel (0.040-0.063 mm) with toluene aseluant, yielding 19.5 g (55% of the theoretical yield) of2,2-dimethyl-6-fluoro-2H-chromene in the form of a light-yellow oil.

40.6 g (0.2 mol) of m-chloroperbenzoic acid are added, while stirring atfrom 15° to 20°, to a solution of 17.8 g (0.1 mol) of2,2-dimethyl-6-fluoro-2H-chromene in 300 ml of trichloromethane. 17.1 g(0.15 mol) of trifluoroacetic acid are added rapidly to the resultingsuspension at room temperature. The reaction mixture is then stirred atroom temperature for 2 hours and then an aqueous solution of sodiumsulfite/sodium hydrogen carbonate (1:1) is added thereto. The organicphase is separated off, washed in succession with water and saturatedsodium chloride solution, dried over sodium sulfate and concentrated byevaporation in vacuo. The resulting residue is subjected to bulb tubedistillation under a high vacuum at 160°. The distillate is dissolved indiethyl ether and the solution is washed in succession with sodiumhydrogen carbonate solution and saturated sodium chloride solution,dried over sodium sulfate and again concentrated by evaporation invacuo. The resulting oily residue is chromatographed on 500 g of silicagel (0.040- 0.063 mm) with toluene as eluant, yielding 7.76 g (40% ofthe theoretical yield) of 2,2-dimethyl-6-fluoro-3-oxo-chroman in theform of a light-yellow oil.

While stirring at from 0° to 5°, a solution of 5.7 g (29 mmol) of2,2-dimethyl-6-fluoro-3-oxo-chroman in 100 ml of absolutetetrahydrofuran is added dropwise within a period of 30 minutes to asuspension of 1.69 g (35 mmol) of sodium hydride dispersion (55% inmineral oil), which has been substantially freed of mineral oilbeforehand by repeated washing with n-hexane, in 100 ml of absolutetetrahydrofuran. The mixture is then stirred at from 0° to 5° for 30minutes and then a solution of 7.9 g (35 mmol) of phosphonoacetic acidtriethyl ester of the formula (H₅ C₂ O)₂ P(═O)CH₂ C(═O)OC₂ H₅ in 70 mlof absolute tetrahydrofuran is added dropwise thereto within a period of30 minutes at from 0° to 5°. The reaction mixture is stirred for afurther 30 minutes at from 0° to 5° and then for 16 hours at roomtemperature and then poured into 700 ml of cold phosphate buffersolution (pH=6). The resulting mixture is extracted with diethyl ether.The combined organic phases are washed in succession with phosphatebuffer solution (pH=7) and water, dried over sodium sulfate andconcentrated by evaporation. The resulting red oil is chromatographed on400 g of silica gel (0.040-0.063 mm) with toluene as eluant, yielding5.76 g (75% of the theoretical yield) of3-ethoxycarbonylmethyl-2,2-dimethyl-6-fluoro-2H-chromene in the form ofan orange-coloured oil.

140 mg of palladium-on-carbon (5%) are added to a solution of 3.4 g (13mmol) of 3-ethoxycarbonylmethyl-2,2-dimethyl-6-fluoro-2H-chromene in 30ml of absolute ethanol and the mixture is hydrogenated at normalpressure and room temperature for 90 minutes. The catalyst is thenfiltered off and the filtrate is concentrated by evaporation in vacuo,yielding 3.47 g of 3-ethoxycarbonylmethyl-2,2-dimethyl-6-fluoro-chromanin the form of a light-yellow oil.

A solution of 3.4 g (12.7 mmol) of3-ethoxycarbonylmethyl-2,2-dimethyl-6-fluoro-chroman in 40 ml ofabsolute diethyl ether is added dropwise within a period of 30 minutes,while cooling with ice, to a suspension of 0.97 g (25.5 mmol) of lithiumaluminium hydride in 30 ml of absolute diethyl ether. The reactionmixture is then stirred for 2 hours at room temperature and thencarefully decomposed with 1 ml of water, 1 ml of sodium hydroxidesolution (15%) and 3 ml of water. The resulting precipitate is filteredoff with suction and the filtrate is dried over sodium sulfate andconcentrated by evaporation in vacuo, yielding 2.75 g (96% of thetheoretical yield) of 2,2-dimethyl-6-fluoro-3-(2-hydroxyethyl)-chromanin the form of a light-yellow oil.

4.01 g (21 mmol) of 4-toluenesulfonyl chloride are added while stirringat room temperature to a solution of 4.48 g (20 mmol) of2,2-dimethyl-6-fluoro-3-(2-hydroxyethyl)-chroman in 30 ml of absolutepyridine, the slightly exothermic reaction being maintained at roomtemperature with an ice bath. The reaction mixture is then stirred atroom temperature for 2 hours, then poured onto ice-water and the mixtureis extracted with diethyl ether. The combined organic phases are washedwhile cold with 2N hydrochloric acid and then with water, dried oversodium sulfate and concentrated by evaporation in vacuo, yielding 6.5 g(85.8% of the theoretical yield) of2,2-dimethyl-6-fluoro-3-[2-(4-toluenesulfonyloxy)ethyl]-chroman in theform of a light-yellow oil.

A solution of 1.62 g (24.9 mmol) of sodium azide in 10 ml of water isadded to a solution of 6.3 g (16.6 mmol) of2,2-dimethyl-6-fluoro-3-[2-(4-toluenesulfonyloxy)-ethyl]-chroman in 100ml of ethanol. The mixture is boiled under reflux for 18 hours. Aftercooling, the ethanol is evaporated off in vacuo and water is added tothe residue. The aqueous mixture is extracted with diethyl ether. Thecombined organic phases are washed with water, dried over sodium sulfateand concentrated by evaporation in vacuo, yielding 4.13 g (100% of thetheoretical yield) of 3-(2-azidoethyl)-2,2-dimethyl-6-fluoro-chroman inthe form of a light-yellow oil.

A solution of 4.0 g (16 mmol) of3-(2-azidoethyl)-2,2-dimethyl-6-fluoro-chroman in 30 ml of absolutetetrahydrofuran is added dropwise within a period of 30 minutes to asuspension of 0.61 g (16 mmol) of lithium aluminium hydride in 30 ml ofabsolute diethyl ether. The reaction mixture is then stirred for 2 hoursat room temperature and then carefully decomposed with 0.61 ml of water,0.61 ml of sodium hydroxide solution (15%) and 1.83 ml of water. Theresulting precipitate is filtered off with suction and the filtrate isconcentrated by evaporation in vacuo. The oily residue is dissolved indiethyl ether and the solution is extracted with 2N hydrochloric acid.The combined hydrochloric acid extracts are rendered alkaline withsodium hydroxide solution (30%) while cooling with ice and extractedwith dichloromethane. The combined dichloromethane phases are dried oversodium sulfate and concentrated by evaporation in vacuo, yielding 3.21 g(90% of the theoretical yield) of 3-(2-aminoethyl)-2,2-dimethyl-6-fluoro-chroman in the form of a yellow oil.3-(2-aminoethyl)-2,2-dimethyl-6-fluoro-chroman hydrochloride, preparedtherefrom with hydrochloric acid in diethyl ether, crystallises frommethanol/diethyl ether and has a melting range of from 249° to 251°.

EXAMPLE 43

In a manner analogous to that described in Examples 38 to 42, it is alsopossible to prepare each of the following compounds or a salt thereof:

N-(2,2-dimethylchroman-3-ylmethyl)-N-(2-methoxycarbonylethyl)-amine;

N-(2,2-dimethylchroman-3-yl)-N-(2-methoxycarbonylethyl)-amine;

N-[2-(6-cyano-2,2-dimethyl-chroman-3-yl)-ethyl]-N-(2-methoxycarbonylethyl)-amine;

3-[N-(2-(2,2-dimethylchroman-3-yl)-ethyl)-amino]-propionic acidmorpholide;

1-[2-(2,2-dimethyl-6-fluoro-chroman-3-yl)-ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylicacid methyl ester, and

1-[2-(6-cyano-2,2-dimethyl-chroman-3-yl)-ethyl]-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylicacid methyl ester or

1-[2-(6-cyano-2,2-dimethyl-chroman-3-yl)-ethyl]-4-oxo-piperidine-3-carboxylicacid methyl ester, respectively.

EXAMPLE 44

While stirring at a temperature of from 0° to 5°, a solution of 1.42 g(16.4 mmol) of acrylic acid methyl ester in 10 ml of methanol is addeddropwise within a period of 15 minutes to a solution of 3.0 g (16.5mmol) of 3-aminomethyl-6-fluoro-chroman in 80 ml of methanol. Thereaction mixture is then stirred for 16 hours at from 0° to 5° and thenconcentrated by evaporation in vacuo. The oily residue ischromatographed on 250 g of silica gel (0.040-0.063 mm) with ethylacetate as eluant, yielding 2.85 g ofN-[(6-fluorochroman-3-yl)methyl]-N-(2-methoxycarbonylethyl)-amine in theform of a light-yellow oil. TheN-[(6-fluorochroman-3-yl)methyl]-N-(2-methoxycarbonylethyl)-aminehydrochloride, prepared therefrom with hydrochloric acid in diethylether, crystallizes from acetone/diethyl ether and melts at 163°-165°.The N-[(6-fluorochroman-3-yl)methyl]-N-(2-methoxycarbonylethyl)-aminecyclamate, prepared from the crude base with N-cyclohexyl-sulfamic acid,crystallizes from acetone and melts at 155°-156°.

The 3-aminomethyl-6-fluoro-chroman can be prepared, for example, asfollows:

While stirring at room temperature, 5.74 g (0.051 mol) of1,4-diazabicyclo[2.2.2]octane (DABCO) are added to a solution of 17.92 g(0.128 mol) of 5-fluoro-2-hydroxy-benzaldehyde (example 42) in 42 ml(0.639 mol) of acrylonitrile. The reaction mixture is then stirred for16 hours at 90°.

After cooling to room temperature, the mixture is diluted with 50 ml ofdiethyl ether and then washed in succession with 2N sodium hydroxidesolution and water. The organic phase is dried over sodium sulfate andconcentrated to dryness by evaporation in vacuo. The resulting redcrystals (22 g) are recrystallized from methanol, yielding 13.3 g of3-cyano-6-fluoro-2H-chromene in the form of light-yellow crystals whichmelt at 97°-100°.

In an argon atmosphere, a mixture of 0.89 g (6.66 mmol) of aluminiumtrichloride in 40 ml of absolute diethyl ether is added dropwise whilestirring at room temperature to a suspension of 1.52 g (40 mmol) oflithium aluminium hydride in 50 ml of absolute diethyl ether.Subsequently, a solution of 3.5 g (20 mmol) of3-cyano-6-fluoro-2H-chromene in 50 ml of absolute tetrahydrofuran isadded dropwise within a period of 20 minutes to the diethyl ethersolution. The reaction mixture is then boiled under reflux for 16 hours.After cooling to room temperature, the reaction mixture is carefullydecomposed with 1.52 ml of water, 1.52 ml of sodiumhydroxide solution(15%) and 4.6 ml of water. The resulting precipitate is filtered offwith suction and the filtrate is concentrated by evaporation in vacuo.The oily residue is dissolved in diethyl ether and the etheral solutionis washed with water and then extracted with 2N hydrochloric acid. Thecombined hydrochloric acid extracts are rendered alkaline with sodiumhydroxide solution (30%) while cooling and extracted withdichloromethane. The combined dichloromethane phases are dried oversodium sulfate and concentrated by evaporation in vacuo, yielding 1.89 gof 3-aminomethyl-6-fluoro-chroman in the form of a light-yellow oil.3-Aminomethyl-6-fluoro-chroman hydrochloride, prepared therefrom withhydrochloric acid in diethyl ether, crystallizes from methanol/acetoneand has a melting range of from 208° to 211°.

EXAMPLE 45

3 g (100 mmol) ofN-[2-(chroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochloride(example 4) are added to 20 ml of 5.5N methanolic ammonia solution. Themixture is stirred in a bomb tube for 12 hours at 60°. Subsequently, thereaction mixture is concentrated by evaporation, the resulting residueis dissolved in 2N hydrochloric acid, and the acidic solution isextracted with diethyl ether. The acidic aqueous phase is renderedalkaline with 2N sodium hydroxide solution and extracted with diethylether. The combined ethereal phases are washed in succession with waterand saturated sodium chloride solution, dried over magnesium sulfate,and concentrated by evaporation, yielding the crude base in the form ofan oil. The crude base is dissolved in a small amount of isopropanol.Ethereal hydrochloric acid is added to the isopropanol solution untilthe mixture gives a weakly acidic reaction. The precipitate is filteredoff and recrystallized from isopropanol/diethyl ether, yielding 0.6 g ofN-(2-aminocarbonylethyl)-N-[2-(chroman-3-yl)ethyl]amine hydrochloridemelting at 220° to 222°.

EXAMPLE 46

Tablets, containing 25 mg of active ingredient, for exampleN-[2-(2,2-dimethylchroman-3-yl)-ethyl]-N-(2-methoxycarbonylethyl)-aminehydrochloride, can be prepared as follows:

    ______________________________________                                        Constituents (for 1000 tablets):                                              ______________________________________                                        active ingredient    25.0 g                                                   lactose              100.7 g                                                  wheat starch         7.5 g                                                    polyethylene glycol 6000                                                                           5.0 g                                                    talc                 5.0 g                                                    magnesium stearate   1.8 g                                                    demineralised water  q.s.                                                     ______________________________________                                    

Preparation

All the solid ingredients are first forced through a sieve of 0.6 mmmesh width. Then the active ingredient, the lactose, the talc, themagnesium stearate and half the starch are mixed together. The otherhalf of the starch is suspended in 40 ml of water and this suspension isadded to a boiling solution of the polyethylene glycol in 100 ml ofwater. The resulting starch paste is added to the main mixture and themixture is granulated, if necessary with the addition of water. Thegranulate is dried overnight at 35°, forced through a sieve of 1.2 mmmesh width and compressed to form tablets of approximately 6 mm diameterthat are concave on both sides.

EXAMPLE 47

Tablets, containing 50 mg of active ingredient, for example1-(benzo-1,4-dioxan-2-ylmethyl)-piperidine-3-carboxylic acid methylester hydrochloride, are prepared as follows:

    ______________________________________                                        Constituents (for 10,000 tablets):                                            ______________________________________                                        active ingredient    500.00 g                                                 lactose              140.80 g                                                 potato starch        274.70 g                                                 stearic acid          10.00 g                                                 talc                  50.00 g                                                 magnesium stearate    2.50 g                                                  colloidal silica      32.00 g                                                 ethanol              q.s.                                                     ______________________________________                                    

A mixture of the active ingredient, the lactose and 194.70 g of potatostarch is moistened with an ethanolic solution of the stearic acid andgranulated through a sieve. After drying, the remaining potato starch,the talc, the magnesium stearate and the colloidal silica are mixed inand the mixture is compressed to form tablets each weighing 0.1 g which,if desired, may be provided with dividing notches for more accurateadaptation of the dose.

100 mg of active ingredient can be incorporated in analogous manner.

EXAMPLE 48

Capsules, containing 0.025 g of active ingredient, for exampleN-[2-(chroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)-aminehydrochloride, can be prepared as follows:

    ______________________________________                                        Constituents (for 1000 capsules):                                             ______________________________________                                        active ingredient    25.00 g                                                  lactose              249.00 g                                                 gelatine              2.00 g                                                  corn starch          10.00 g                                                  talc                 15.00 g                                                  water                q.s.                                                     ______________________________________                                    

The active ingredient is mixed with the lactose and the mixture ismoistened uniformly with an aqueous solution of the gelatine andgranulated through a sieve of 1.2 to 1.5 mm mesh width. The granulate ismixed with the dried corn starch and the talc and is introduced in 300mg portions into hard gelatine capsules (size 1).

EXAMPLE 49

In a manner analogous to that described in Examples 46 to 48 it is alsopossible to prepare pharmaceutical preparations containing as activeingredient a different compound of formula I or a tautomer and/or apharmaceutically acceptable salt thereof or a different compound offormula IVc or a pharmaceutically acceptable salt thereof, for exampleaccording to Examples 1 to 45.

We claim:
 1. A compound of the formula ##STR34## in which R₁ representsa carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl,N,N-di-lower alkylcarbamoyl, hydroxymethyl, lower alkanoyloxymethyl,lower alkanesulphonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl,R₃represents hydrogen or lower alkyl, alk represents lower alkylene thatlinks the ring system with the NH group shown in formula (IVcA) by up toand including 3 carbon atoms or alk represents lower alkylidene, thering A is unsubstituted or is mono-, di- or poly-substituted bysubstituents selected from the group consisting of hydroxy, loweralkoxy, lower alkanoyloxy, halogen, lower alkyl and trifluoromethyl andeither(a) X represents a methylene group, Y represents an oxygen atomand n represents 1 or (b) X represents an oxygen atom, Y represents amethylene group and n represents 1 or (c) X represents a direct bond, Yrepresents an oxygen atom and n represents 2, or a pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1 of theformula IVcA in which R₁ represents carboxy, lower alkoxycarbonyl,carbamoyl, N-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl,R₃represents hydrogen or lower alkyl, alk represents lower alkylene thatlinks the ring system with the NH group shown in formula IVcA by up toand including 3 carbon atoms, or alk represents lower alkylidene, thering A is unsubstituted or is mono-, di- or poly-substituted bysubstituents selected from the group consisting of hydroxy, loweralkoxy, lower alkanoyloxy, halogen, lower alkyl and trifluoromethyl, Xrepresents a methylene group, Y represents an oxygen atom and nrepresents 1,or a pharmaceutically acceptable salt thereof.
 3. Acompound according to claim 1 of the formula IVcA, in which R₁represents carboxy, hydroxymethyl, C₂ -C₅ alkanoyloxymethyl, C₁ -C₄alkoxycarbonyl or carbamoyl,R₃ represents hydrogen or C₁ -C₄ alkyl, alkrepresents C₁ -C₄ alkylene that links the ring system with the NH groupshown in formula IVcA by up to and including 3 carbon atoms, the ring Ais unsubstituted or substituted by C₁ -C₄ alkoxy, and either(a) Xrepresents a methylene group, Y represents an oxygen atom and nrepresents 1 or (b) X represents an oxygen atom, Y represents amethylene group and n represents 1 or (c) X represents a direct bond, Yrepresents an oxygen atom and n represents 2,or a pharmaceuticallyacceptable salt thereof.
 4. A compound according to claim 1 of theformula IVcA in which R₁ represents C₁ -C₄ alkoxycarbonyl,R₃ representshydrogen or C₁ -C₄ alkyl, alk represents C₁ -C₄ alkylene that links thering system with the NH group shown in formula IVcA by up to andincluding 3 carbon atoms, the ring A is unsubstituted, X represents amethylene group, Y represents an oxygen atom, and n represents 1,or apharmaceutically acceptable salt thereof.
 5. A compound according toclaim 1 beingN-[2-(chroman-3-yl)-ethyl]-N-(2-methoxycarbonylethyl)-amine or apharmaceutically acceptable salt thereof.
 6. A compound according toclaim 1 being N-(2-aminocarbonylethyl)-N-[2-(chroman-3-yl)ethyl]-amineor a pharmaceutically acceptable salt thereof.
 7. A compound accordingto claim 1 beingN-[(6-fluorochroman-3-yl)-methyl]-N-(2-methoxycarbonylethyl)-amine or apharmaceutically acceptable salt thereof.
 8. A pharmaceuticalpreparation comprising a nootropically effective amount of a compoundaccording to claim 1 or of a pharmaceutically acceptable salt thereof,together with a pharmaceutically acceptable adjunct.
 9. Method for thetreatment of the symptoms of cerebral insufficiency, characterised inthat a nootropically effective amount of a compound according to claim 1in free form or in form of a pharmaceutically acceptable salt, isadministered a subject in need of such treatment.